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Research Program on Genes, Environment and Health - RPGEH Publications

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. Supported by the Welsh Government and Fight for Sight (24WG201).

Authors: Clark, Rosie; Choquet, Hélène; UK Biobank Eye and Vision Consortium,; et al.

EBioMedicine. 2023 May;91:104551. Epub 2023-04-11.

PubMed abstract

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method “SKAT-O,” we tested the association between candidate genes and POMS risk. After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Authors: Horton, Mary K; Schaefer, Catherine; Barcellos, Lisa F; et al.

Mult Scler. 2023 Apr;29(4-5):505-511. Epub 2023-02-08.

PubMed abstract

Genetically Predicted Serum Vitamin C Levels and Cutaneous Squamous Cell Carcinoma Risk

Authors: Kim, Yuhree; Yin, Jie; Le Breton, Stephen; Jorgenson, Eric; Huang, Hailiang; Choquet, Hélène; Asgari, Maryam M

J Invest Dermatol. 2023 Apr;143(4):664-667. Epub 2022-11-05.

PubMed abstract

A Cross-Trait, Mendelian Randomization Study to Investigate Whether Migraine Is a Risk Factor for Multiple Sclerosis

Migraine is common among people with multiple sclerosis (MS), but the reasons for this are unknown. We tested 3 hypothesized mechanisms for this observed comorbidity, including migraine is a risk factor of MS, genetic variants are shared between the conditions, and migraine is because of MS. Data were from 2 sources: publicly available summary statistics from genome-wide association studies of MS (N = 115,748) and migraine (N = 375,752 and N = 361,141) and a case-control study of MS recruited from the Kaiser Permanente Northern California Health Plan (N = 1,991). For the latter participants, migraine status was ascertained using a validated electronic health record migraine probability algorithm or self-report. Using the public summary statistics, we used 2-sample Mendelian randomization to test whether a migraine genetic instrumental variable was associated with MS. We used linkage disequilibrium score regression and LOGODetect to ascertain whether MS and migraine shared genetic variants across the genome and regionally. Using the Northern California MS cohort, we used logistic regression to identify whether people with both MS and migraine had different odds of clinical characteristics (e.g., age at MS onset, Perceived Deficits Questionnaire, and depression) or MS-specific risk factors (e.g., body mass index, smoking status, and infectious mononucleosis status) compared with people with MS without migraine. We did not find evidence supporting migraine as a causal risk factor of MS (p = 0.29). We did, however, identify 4 major histocompatibility complex (MHC) loci shared between MS and migraine. Among the Northern California MS cohort, 774 (39%) experienced migraine. People with both MS and migraine from this cohort were more likely to ever smoke (odds ratio [OR] = 1.30, 95% CI: 1.08-1.57), have worse self-reported cognitive deficits (OR = 1.04, 95% CI: 1.02-1.06), and ever experience depression (OR = 1.48, 95% CI: 1.22-1.80). Our findings do not support migraine as a causal risk factor of MS. Several genetic variants, particularly in the MHC, may account for some of the overlap. It seems likely that migraine within the context of MS is because of MS. Identifying what increases the risk of migraine within MS might lead to an improved treatment and quality of life.

Authors: Horton, Mary K; Schaefer, Catherine A; Barcellos, Lisa F; et al.

Neurology. 2023 Mar 28;100(13):e1353-e1362. Epub 2023-01-11.

PubMed abstract

Association of Education With Dementia Incidence Stratified by Ethnicity and Nativity in a Cohort of Older Asian American Individuals

High education protects against dementia, but returns on educational attainment may be different across sociodemographic groups owing to various social factors. Asian American individuals are a growing and diverse group, but little research has assessed dementia determinants in this population. To examine the association of education with dementia in a large cohort of Asian American individuals, stratifying by ethnicity and nativity. This cohort study used electronic health record (EHR) and survey data from the Research Program on Genes, Environment, and Health and the California Men’s Health Study surveys (2002-2020). Data are from Kaiser Permanente Northern California, an integrated health care delivery system. This study used a volunteer sample who completed the surveys. Participants included Chinese, Filipino, and Japanese individuals who were aged 60 to less than 90 years without a dementia diagnosis in the EHR at the time of the survey (baseline) and who had 2 years of health plan coverage before baseline. Data analysis was performed from December 2021 to December 2022. The main exposure was educational attainment (college degree or higher vs less than a college degree), and the main stratification variables were Asian ethnicity and nativity (born in the US or born outside the US). The primary outcome was incident dementia diagnosis in the EHR. Dementia incidence rates were estimated by ethnicity and nativity, and Cox proportional hazards and Aalen additive hazards models were fitted for the association of college degree or higher vs less than a college degree with time to dementia, adjusting for age (timescale), sex, nativity, and an interaction between nativity and college degree. Among 14 749 individuals, the mean (SD) age at baseline was 70.6 (7.3) years, 8174 (55.4%) were female, and 6931 (47.0%) had attained a college degree. Overall, among individuals born in the US, those with a college degree had 12% lower dementia incidence (HR, 0.88; 95% CI, 0.75-1.03) compared with those without at least a college degree, although the confidence interval included the null. The HR for individuals born outside the US was 0.82 (95% CI, 0.72-0.92; P = .46 for the college degree by nativity interaction). The findings were similar across ethnicity and nativity groups except for Japanese individuals born outside the US. These findings suggest that college degree attainment was associated with lower dementia incidence, with similar associations across nativity. More work is needed to understand determinants of dementia in Asian American individuals and to elucidate mechanisms linking educational attainment and dementia.

Authors: Hayes-Larson, Eleanor; Ikesu, Ryo; Fong, Joseph; Mobley, Taylor M; Gee, Gilbert C; Brookmeyer, Ron; Whitmer, Rachel A; Gilsanz, Paola; Mayeda, Elizabeth Rose

JAMA Netw Open. 2023 Mar 01;6(3):e231661. Epub 2023-03-01.

PubMed abstract

Polygenic risk score association with multiple sclerosis susceptibility and phenotype in Europeans

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.

Authors: Shams, Hengameh; Schaefer, Catherine; Oksenberg, Jorge R; et al.

Brain. 2023 Feb 13;146(2):645-656.

PubMed abstract

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis

Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

Authors: Watts, Eleanor L; Schaefer, Catherine A; Van Den Eeden, Stephen K; Travis, Ruth C; et al.

Int J Epidemiol. 2023 Feb 08;52(1):71-86.

PubMed abstract

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Authors: Saunders, Gretchen R B; Choquet, Hélène; Vrieze, Scott; et al.

Nature. 2022 Dec;612(7941):720-724. Epub 2022-12-07.

PubMed abstract

Association Between Myopic Refractive Error and Primary Open-Angle Glaucoma: A 2-Sample Mendelian Randomization Study

Refractive error (RE) is the most common form of visual impairment, and myopic RE is associated with an increased risk of primary open-angle glaucoma (POAG). Whether this association represents a causal role of RE in the etiology of POAG remains unknown. To evaluate shared genetic influences and investigate the association of myopic RE with the risk for POAG. Observational analyses were used to evaluate the association between mean spherical equivalent (MSE) RE (continuous trait) or myopia (binary trait) and POAG risk in individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. To quantify genetic overlap, genome-wide genetic correlation analyses were performed using genome-wide association studies (GWAS) of MSE RE or myopia and POAG from GERA. Potential causal effects were assessed between MSE RE and POAG using 2-sample Mendelian randomization. Genetic variants associated with MSE RE were derived using GWAS summary statistics from a GWAS of RE conducted in 102 117 UK Biobank participants. For POAG, we used GWAS summary statistics from our previous GWAS (3836 POAG cases and 48 065 controls from GERA). Data analyses occurred between July 2020 and October 2021. Our main outcome was POAG risk as odds ratio (OR) caused by per-unit difference in MSE RE (in diopters). Our observational analyses included data for 54 755 non-Hispanic White individuals (31 926 [58%] females and 22 829 [42%] males). Among 4047 individuals with POAG, mean (SD) age was 73.64 (9.20) years; mean (SD) age of the 50 708 controls was 65.38 (12.24) years. Individuals with POAG had a lower refractive MSE and were more likely to have myopia or high myopia compared with the control participants (40.2% vs 34.1%, P = 1.31 × 10-11 for myopia; 8.5% vs 6.8%, P = .004 for high myopia). Our genetic correlation analyses demonstrated that POAG was genetically correlated with MSE RE (rg, -0.24; SE, 0.06; P = 3.90 × 10-5), myopia (rg, 0.21; SE, 0.07; P = .004), and high myopia (rg, 0.23; SE, 0.09; P = .01). Genetically assessed refractive MSE was negatively associated with POAG risk (inverse-variance weighted model: OR per diopter more hyperopic MSE = 0.94; 95% CI, 0.89-0.99; P = .01). These findings demonstrate a shared genetic basis and an association between myopic RE and POAG risk. This may support population POAG risk stratification and screening strategies, based on RE information.

Authors: Choquet, Hélène; Khawaja, Anthony P; Jiang, Chen; Yin, Jie; Melles, Ronald B; Glymour, M Maria; Hysi, Pirro G; Jorgenson, Eric

JAMA Ophthalmol. 2022 Sep 01;140(9):864-871.

PubMed abstract

Modest effect of statins on fasting glucose in a longitudinal electronic health record based cohort

Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels. Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years’ supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users. We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types. Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.

Authors: Haldar, Tanushree; Oni-Orisan, Akinyemi; Hoffmann, Thomas J; Schaefer, Catherine; Iribarren, Carlos; Krauss, Ronald M; Medina, Marisa W; Risch, Neil

Cardiovasc Diabetol. 2022 Jul 14;21(1):132. Epub 2022-07-14.

PubMed abstract

Ancestry- and sex-specific effects underlying inguinal hernia susceptibility identified in a multiethnic genome-wide association study meta-analysis

Inguinal hernias are some of the most frequently diagnosed conditions in clinical practice and inguinal hernia repair is the most common procedure performed by general surgeons. Studies of inguinal hernias in non-European populations are lacking, though it is expected that such studies could identify novel loci. Further, the cumulative lifetime incidence of inguinal hernia is nine times greater in men than women, however, it is not clear why this difference exists. We conducted a genome-wide association meta-analysis of inguinal hernia risk across 513 120 individuals (35 774 cases and 477 346 controls) of Hispanic/Latino, African, Asian and European descent, with replication in 728 418 participants (33 491 cases and 694 927 controls) from the 23andMe, Inc dataset. We identified 63 genome-wide significant loci (P < 5 × 10-8), including 41 novel. Ancestry-specific analyses identified two loci (LYPLAL1-AS1/SLC30A10 and STXBP6-NOVA1) in African ancestry individuals. Sex-stratified analyses identified two loci (MYO1D and ZBTB7C) that are specific to women, and four (EBF2, EMX2/RAB11FIP2, VCL and FAM9A/FAM9B) that are specific to men. Functional experiments demonstrated that several of the associated regions (EFEMP1 and LYPLAL1-SLC30A10) function as enhancers and show differential activity between risk and reference alleles. Our study highlights the importance of large-scale genomic studies in ancestrally diverse populations for identifying ancestry-specific inguinal hernia susceptibility loci and provides novel biological insights into inguinal hernia etiology.

Authors: Choquet, Hélène; Li, Weiyu; Yin, Jie; Bradley, Rachael; Hoffmann, Thomas J; Nandakumar, Priyanka; 23andMe Research Team,; Mostaedi, Rouzbeh; Tian, Chao; Ahituv, Nadav; Jorgenson, Eric

Hum Mol Genet. 2022 07 07;31(13):2279-2293.

PubMed abstract

GWAS identifies two common loci associated with pigment dispersion syndrome/pigmentary glaucoma and implicate myopia in its development

To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. A total of 574 cases with PG or PDS and 52 627 controls of European descent. Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10-7). Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

Authors: Simcoe, Mark J; Choquet, Hélène; Hammond, Christopher J; et al.

Ophthalmology. 2022 06;129(6):626-636. Epub 2022-01-11.

PubMed abstract

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Authors: Palmer, Duncan S; Schaefer, Catherine; Scott, Laura; Neale, Benjamin M; et al.

Nat Genet. 2022 05;54(5):541-547. Epub 2022-04-11.

PubMed abstract

Genome-wide association study of actinic keratosis identifies new susceptibility loci implicated in pigmentation and immune regulation pathways

Actinic keratosis (AK) is a common precancerous cutaneous neoplasm that arises on chronically sun-exposed skin. AK susceptibility has a moderate genetic component, and although a few susceptibility loci have been identified, including IRF4, TYR, and MC1R, additional loci have yet to be discovered. We conducted a genome-wide association study of AK in non-Hispanic white participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (n = 63,110, discovery cohort), with validation in the Mass-General Brigham (MGB) Biobank cohort (n = 29,130). We identified eleven loci (P < 5 × 10-8), including seven novel loci, of which four novel loci were validated. In a meta-analysis (GERA + MGB), one additional novel locus, TRPS1, was identified. Genes within the identified loci are implicated in pigmentation (SLC45A2, IRF4, BNC2, TYR, DEF8, RALY, HERC2, and TRPS1), immune regulation (FOXP1 and HLA-DQA1), and cell signaling and tissue remodeling (MMP24) pathways. Our findings provide novel insight into the genetics and pathogenesis of AK susceptibility.

Authors: Kim, Yuhree; Yin, Jie; Huang, Hailiang; Jorgenson, Eric; Choquet, Hélène; Asgari, Maryam M

Commun Biol. 2022 Apr 21;5(1):386. Epub 2022-04-21.

PubMed abstract

Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI’s Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Authors: Little, Amarise; Correa, Adolfo; Raffield, Laura M; et al.

Hum Mol Genet. 2022 02 03;31(3):347-361.

PubMed abstract

Full title: A large-scale transcriptome-wide association study (TWAS) of 10 blood cell phenotypes reveals complexities of TWAS fine-mapping

Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.

Authors: Tapia, Amanda L; Choquet, Hélène; Raffield, Laura M; et al.

Genet Epidemiol. 2022 02;46(1):3-16. Epub 2021-11-15.

PubMed abstract

Case-control study of adverse childhood experiences and multiple sclerosis risk and clinical outcomes

Adverse childhood experiences (ACEs) are linked to numerous health conditions but understudied in multiple sclerosis (MS). This study’s objective was to test for the association between ACEs and MS risk and several clinical outcomes. We used a sample of adult, non-Hispanic MS cases (n = 1422) and controls (n = 1185) from Northern California. Eighteen ACEs were assessed including parent divorce, parent death, and abuse. Outcomes included MS risk, age of MS onset, Multiple Sclerosis Severity Scale score, and use of a walking aid. Logistic and linear regression estimated odds ratios (ORs) (and beta coefficients) and 95% confidence intervals (CIs) for ACEs operationalized as any/none, counts, individual events, and latent factors/patterns. Overall, more MS cases experienced ≥1 ACE compared to controls (54.5% and 53.8%, respectively). After adjusting for sex, birthyear, and race, this small difference was attenuated (OR = 1.01, 95% CI: 0.87, 1.18). There were no trends of increasing or decreasing odds of MS across ACE count categories. Consistent associations between individual ACEs between ages 0-10 and 11-20 years and MS risk were not detected. Factor analysis identified five latent ACE factors, but their associations with MS risk were approximately null. Age of MS onset and other clinical outcomes were not associated with ACEs after multiple testing correction. Despite rich data and multiple approaches to operationalizing ACEs, no consistent and statistically significant effects were observed between ACEs with MS. This highlights the challenges of studying sensitive, retrospective events among adults that occurred decades before data collection.

Authors: Horton, Mary K; McCurdy, Shannon; Shao, Xiaorong; Bellesis, Kalliope; Chinn, Terrence; Schaefer, Catherine; Barcellos, Lisa F

PLoS One. 2022;17(1):e0262093. Epub 2022-01-13.

PubMed abstract

Hereditary Spherocytosis

Hereditary spherocytosis (HS) is the most prevalent cause of hemolytic anemia due to an abnormal red cell membrane and classifies as a type of congenital hemolytic anemia. Oskar Minkowsky first described it in the early 1900s.[1] Erythrocytes are unable to maintain their normal biconcave shape due to genetic mutations in membrane/cytoskeletal proteins that play a role in structural morphologic stability. Deficient or abnormal proteins may include spectrin, ankyrin, band 3, and band 4.2, encoded by different genes.[2][3] The clinical manifestations vary based on the severity of disease and the type of genetic mutation.[1][2][3]

Authors: Zamora, Edgar A.; Schaefer, Catherine A.

Treasure Island (FL): StatPearls Publishing; 2022.

PubMed abstract

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Authors: Mikhaylova, Anna V; Choquet, Hélène; Auer, Paul L; et al.

Am J Hum Genet. 2021 10 07;108(10):1836-1851. Epub 2021-09-27.

PubMed abstract

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Authors: Jia, Xiaoming; Schaefer, Catherine; Scott, Laura J; et al.

Mol Psychiatry. 2021 09;26(9):5239-5250. Epub 2021-01-22.

PubMed abstract

GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

Authors: Nair, K Saidas; Choquet, H�l�ne; Jetten, Anton M; et al.

Nat Commun. 2021 08 12;12(1):4877. Epub 2021-08-12.

PubMed abstract

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.

Authors: Choquet, Hélène; Yin, Jie; Jacobson, Alice S; Horton, Brandon H; Hoffmann, Thomas J; Jorgenson, Eric; Avins, Andrew L; Pressman, Alice R

Commun Biol. 2021 07 22;4(1):864. Epub 2021-07-22.

PubMed abstract

Transcriptome-Wide Association Study of Blood Cell Traits in African Ancestry and Hispanic/Latino Populations

Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Our results revealed 24 suggestive signals (p < 1 × 10-4) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

Authors: Wen, Jia; Fornage, Myriam; Li, Yun; et al.

Genes (Basel). 2021 07 08;12(7). Epub 2021-07-08.

PubMed abstract

A large multiethnic GWAS meta-analysis of cataract identifies new risk loci and sex-specific effects

Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.

Authors: Choquet, Hélène; Jorgenson, Eric; et al.

Nat Commun. 2021 06 14;12(1):3595. Epub 2021-06-14.

PubMed abstract

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Authors: Hu, Yao; Choquet, Hélène; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,; et al.

Am J Hum Genet. 2021 05 06;108(5):874-893. Epub 2021-04-21.

PubMed abstract

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Authors: Currant, Hannah; Choquet, Hélène; Khawaja, Anthony P; et al.

PLoS Genet. 2021 05;17(5):e1009497. Epub 2021-05-12.

PubMed abstract

A validation study for remote testing of cognitive function in multiple sclerosis

Determine the validity and reliability of a remote, technician-guided cognitive assessment for multiple sclerosis (MS), incorporating the Symbol Digit Modalities Test (SDMT) and the California Verbal Learning Test, Second Edition (CVLT-II). In 100 patients, we compared conventional in-person testing to remote, web-assisted assessments, and in 36 patients, we assessed test-retest reliability using two equivalent, alternative forms. In-person and remote-administered SDMT (r = 0.85) and CVLT-II (r = 0.71) results were very similar. Reliability was adequate and alternative forms of SDMT (r = 0.92) and CVLT-II (r = 0.81) produced similar results. Findings indicate remote assessment can provide valid, reliable measures of cognitive function in MS.

Authors: Barcellos LF; Horton M; Shao X; Bellesis KH; Chinn T; Waubant E; Bakshi N; Marcus J; Benedict RH; Schaefer C

Mult Scler. 2021 04;27(5):795-798. Epub 2020-07-14.

PubMed abstract

A large-scale association study detects novel rare variants, risk genes, functional elements, and polygenic architecture of prostate cancer susceptibility

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.

Authors: Emami, Nima C; Presti, Joseph; Habel, Laurel A; Sakoda, Lori C; Schaefer, Catherine; Van Den Eeden, Stephen K; Witte, John S; et al.

Cancer Res. 2021 04 01;81(7):1695-1703. Epub 2020-12-08.

PubMed abstract

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Authors: Hardcastle, Alison J; Choquet, Hélène; Hysi, Pirro G; et al.

Commun Biol. 2021 03 01;4(1):266. Epub 2021-03-01.

PubMed abstract

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Authors: Gharahkhani, Puya; Qassim, Ayub; Wiggs, Janey L; et al.

Nat Commun. 2021 02 24;12(1):1258. Epub 2021-02-24.

PubMed abstract

Cigarette smoking behaviors and the importance of ethnicity and genetic ancestry

Cigarette smoking contributes to numerous diseases and is one of the leading causes of death in the United States. Smoking behaviors vary widely across race/ethnicity, but it is not clear why. Here, we examine the contribution of genetic ancestry to variation in two smoking-related traits in 43,485 individuals from four race/ethnicity groups (non-Hispanic white, Hispanic/Latino, East Asian, and African American) from a single U.S. healthcare plan. Smoking prevalence was the lowest among East Asians (22.7%) and the highest among non-Hispanic whites (38.5%). We observed significant associations between genetic ancestry and smoking-related traits. Within East Asians, we observed higher smoking prevalence with greater European (versus Asian) ancestry (P = 9.95 × 10-12). Within Hispanic/Latinos, higher cigarettes per day (CPD) was associated with greater European ancestry (P = 3.34 × 10-25). Within non-Hispanic whites, the lowest number of CPD was observed for individuals of southeastern European ancestry (P = 9.06 × 10-5). These associations remained after considering known smoking-associated loci, education, socioeconomic factors, and marital status. Our findings support the role of genetic ancestry and socioeconomic factors in cigarette smoking behaviors in non-Hispanic whites, Hispanic/Latinos, and East Asians.

Authors: Choquet, Hélène; Yin, Jie; Jorgenson, Eric

Transl Psychiatry. 2021 02 11;11(1):120. Epub 2021-02-11.

PubMed abstract

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

Authors: Oni-Orisan A; Haldar T; Ranatunga DK; Medina MW; Schaefer C; Krauss RM; Iribarren C; Risch N; Hoffmann TJ

NPJ Genom Med. 2020 Jan 16;5(1):1. Epub 2020-01-16.

PubMed abstract

Genetic ancestry, skin pigmentation, and the risk of cutaneous squamous cell carcinoma in Hispanic/Latino and non-Hispanic white populations

Although cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in individuals of European ancestry, the incidence of cSCC in Hispanic/Latinos is also increasing. cSCC has both a genetic and environmental etiology. Here, we examine the role of genetic ancestry, skin pigmentation, and sun exposure in Hispanic/Latinos and non-Hispanic whites on cSCC risk. We observe an increased cSCC risk with greater European ancestry (P = 1.27 × 10-42) within Hispanic/Latinos and with greater northern (P = 2.38 × 10-65) and western (P = 2.28 × 10-49) European ancestry within non-Hispanic whites. These associations are significantly, but not completely, attenuated after considering skin pigmentation-associated loci, history of actinic keratosis, and sun-protected versus sun-exposed anatomical sites. We also report an association of the well-known pigment variant Ala111Thr (rs1426654) at SLC24A5 with cSCC in Hispanic/Latinos. These findings demonstrate a strong correlation of northwestern European genetic ancestry with cSCC risk in both Hispanic/Latinos and non-Hispanic whites, largely but not entirely mediated through its impact on skin pigmentation.

Authors: Jorgenson, Eric; Choquet, Hélène; Yin, Jie; Hoffmann, Thomas J; Banda, Yambazi; Kvale, Mark N; Risch, Neil; Schaefer, Catherine; Asgari, Maryam M

Commun Biol. 2020 12 14;3(1):765. Epub 2020-12-14.

PubMed abstract

Pregnancy does not modify the risk of MS in genetically susceptible women

To use the case-only gene-environment (G [Formula: see text] E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females. We studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) [Formula: see text] live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS. Evidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results. Our findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

Authors: Adams, Cameron J; Schaefer, Catherine; Barcellos, Lisa F; et al.

Neurol Neuroimmunol Neuroinflamm. 2020 11;7(6). Epub 2020-10-09.

PubMed abstract

Identification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10-8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.

Authors: Sieh, Weiva; Alexeeff, Stacey E; Sakoda, Lori C; Risch, Neil; Habel, Laurel A; et al.

Nat Commun. 2020 10 09;11(1):5116. Epub 2020-10-09.

PubMed abstract

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Authors: Chen, Ming-Huei; Choquet, Hélène; Lettre, Guillaume; et al.

Cell. 2020 09 03;182(5):1198-1213.e14.

PubMed abstract

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Authors: Vuckovic, Dragana; Danesh, John; Soranzo, Nicole; et al.

Cell. 2020 09 03;182(5):1214-1231.e11.

PubMed abstract

Associations of CYP2C9 and CYP2C19 pharmacogenetic variation with phenytoin-induced cutaneous adverse drug reactions

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin-induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA-B)*15:02 risk allele. In the multi-ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self-identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non-Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin-induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64-11.69; P < 0.01). Among participants with low-intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin-induced cutaneous adverse events in the absence of the HLA-B*15:02 risk allele.

Authors: Fohner AE; Rettie AE; Thai KK; Ranatunga DK; Lawson BL; Liu VX; Schaefer CA

Clin Transl Sci. 2020 09;13(5):1004-1009. Epub 2020-04-18.

PubMed abstract

Meta-analysis of 26,638 Individuals Identifies Two Genetic Loci Associated with Left Ventricular Ejection Fraction

Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P=3.10×10-8) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=-0.83 and P=8.24×10-17). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequencies<0.05) in Asian and African ancestry populations. These associations were slightly attenuated, after considering antecedent cardiac conditions (ie, heart failure/cardiomyopathy, hypertension, myocardial infarction, atrial fibrillation, valvular disease, and revascularization procedures). This suggests that the effects of the lead variants at TMEM40 or BAG3 on EF are largely independent of these conditions. In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3, associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.

Authors: Choquet H; Thai KK; Jiang C; Ranatunga DK; Hoffmann TJ; Go AS; Lindsay AC; Ehm MG; Waterworth DM; Risch N; Schaefer C

Circ Genom Precis Med. 2020 08;13(4):e002804. Epub 2020-06-30.

PubMed abstract

Analysis of putative cis-regulatory elements regulating blood pressure variation

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of ‘expressed’ genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

Authors: Nandakumar P; Kwok PY; Risch N; Chakravarti A; Chakravarti A; et al.

Hum Mol Genet. 2020 07 21;29(11):1922-1932.

PubMed abstract

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.

Authors: Choquet H; Schaefer C; Risch N; Jorgenson E; et al.

Commun Biol. 2020 06 11;3(1):301. Epub 2020-06-11.

PubMed abstract

Genetic and environmental factors underlying keratinocyte carcinoma risk

Recent large-scale GWAS and large epidemiologic studies have accelerated the discovery of genes and environmental factors that contribute to the risk of keratinocyte carcinoma (KC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This Review summarizes the genomic regions associated with SCC and BCC risk, examines the genetic overlap between SCC and BCC, and discusses biological pathways involved in SCC and BCC development. Next, we review environmental factors that are associated with KC risk, including those that are shared between SCC and BCC as well as others that associated with only one type of KC. We conclude with a critical appraisal of current research and potential directions for future research.

Authors: Choquet H; Ashrafzadeh S; Kim Y; Asgari MM; Jorgenson E

JCI Insight. 2020 05 21;5(10). Epub 2020-05-21.

PubMed abstract

Breastfeeding is associated with reduced risk of multiple sclerosis in males, predominantly among HLA-DRB1*15:01 carriers

Breastfeeding as an infant appears protective against later development of some autoimmune diseases, but research into its influence on multiple sclerosis (MS) risk has yielded inconclusive results. We investigated the possible impact of breastfeeding on MS risk. We used two population-based case-control studies comprising 3670 cases and 6737 matched controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between MS and exposure to prolonged breastfeeding (4 months or longer) versus reduced breastfeeding (less than 4 months). A meta-analysis of case-control studies that assessed the impact of breastfeeding on MS risk among women and men was conducted. Prolonged breastfeeding was associated with reduced MS risk among men (OR 0.7, 95% CI 0.5-0.9) but not among women (OR 0.9, 95% CI 0.8-1.1). Among men, a synergistic effect was observed between HLA-DRB1*15:01 carrier status and reduced breastfeeding. Findings from the current study add to accumulating evidence that breastfeeding may be a modifiable protective factor for reducing the risk of MS in offspring. When possible, mothers should be supported to breastfeed their infants; however, the mechanism of a sex-specific biologic effect of breastfeeding on MS risk is unclear.

Authors: Hedström AK; Adams C; Shao X; Schaefer C; Olsson T; Barcellos LF; Alfredsson L

Mult Scler J Exp Transl Clin. 2020 Apr-Jun;6(2):2055217320928101. Epub 2020-06-01.

PubMed abstract

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Authors: Hysi PG; Khawaja AP; Hammond CJ; et al.

Nat Genet. 2020 04;52(4):401-407. Epub 2020-03-30.

PubMed abstract

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.

Authors: Sarin KY; Wu W; Asgari MM; Han J; et al.

Nat Commun. 2020 Feb 10;11(1):820. Epub 2020-02-10.

PubMed abstract

Functional validity, role, and implications of heavy alcohol consumption genetic loci

High alcohol consumption is a risk factor for morbidity and mortality, yet few genetic loci have been robustly associated with alcohol intake. Here, we use U.K. Biobank (n = 125,249) and GERA (n = 47,967) datasets to determine genetic factors associated with extreme population-level alcohol consumption and examine the functional validity of outcomes using model organisms and in silico techniques. We identified six loci attaining genome-wide significant association with alcohol consumption after meta-analysis and meeting our criteria for replication: ADH1B (lead SNP: rs1229984), KLB (rs13130794), BTF3P13 (rs144198753), GCKR (rs1260326), SLC39A8 (rs13107325), and DRD2 (rs11214609). A conserved role in phenotypic responses to alcohol was observed for all genetic targets available for investigation (ADH1B, GCKR, SLC39A8, and KLB) in Caenorhabditis elegans. Evidence of causal links to lung cancer, and shared genetic architecture with gout and hypertension was also found. These findings offer insight into genes, pathways, and relationships for disease risk associated with high alcohol consumption.

Authors: Thompson A; Cook J; Choquet H; Jorgenson E; Yin J; Kinnunen T; Barclay J; Morris AP; Pirmohamed M

Sci Adv. 2020 Jan;6(3):eaay5034. Epub 2020-01-15.

PubMed abstract

Genome-wide Genotyping of Cerebral Cavernous Malformation Type 1 Individuals to Identify Genetic Modifiers of Disease Severity

Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by brain lesions that can cause hemorrhagic strokes, seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Genetic modifiers of CCM1 disease severity have been recently identified and included common genetic variants in inflammatory, immune response, and oxidative stress genes and pathways. Here, we describe the genotyping of CCM1 patients with the same gene mutation (Q455X) using a high-throughput genotyping array optimized for individuals of Hispanic/Latino ancestry. We then review the quality control steps following the genome-wide genotyping. Genome-wide genotyping of larger cohorts of CCM1 patients might reveal additional genetic variants contributing to the disease severity of CCM1.

Authors: Choquet H; Kim H

Methods Mol Biol. 2020;2152:77-84.

PubMed abstract

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

Authors: Oni-Orisan A; Haldar T; Ranatunga DK; Medina MW; Schaefer C; Krauss RM; Iribarren C; Risch N; Hoffmann TJ

NPJ Genom Med. 2020;5:1. Epub 2020-01-16.

PubMed abstract

Clinical implications of recent advances in primary open-angle glaucoma genetics

Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup-disc ratio (VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available. ??: ?????????(POAG)???????????????, ??????, ?????????, ??????????, ???POAG??????????????????2019?9??????????POAG?????????????????, ??74???????POAG???????????POAG? GWAS????????????????POAG????????????, ?????????????????????????????????, ?????POAG???????????, ??????? (??????????) ??????????????????????????????POAG??????????POAG????????, ???????POAG??????????????????????????POAG????????????????????, ??????????????????????????????????????.

Authors: Choquet H; Wiggs JL; Khawaja AP

Eye (Lond). 2020 01;34(1):29-39. Epub 2019-10-23.

PubMed abstract

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Authors: Watts EL; Habel LA; Schaefer CA; Van Den Eeden SK; Travis RC; et al.

Int J Cancer. 2019 12 15;145(12):3244-3256. Epub 2019-04-04.

PubMed abstract

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8×10-15] in African populations, rs11549407 with lower HGB [p = 1.5×10-12] and HCT [p = 8.8×10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Authors: Kowalski MH; Choquet H; Li Y; et al.

PLoS Genet. 2019 12;15(12):e1008500. Epub 2019-12-23.

PubMed abstract

Contribution of rare coding mutations in CD36 to type 2 diabetes and cardio-metabolic complications

We sequenced coding regions of the cluster of differentiation 36 (CD36) gene in 184 French individuals of European ancestry presenting simultaneously with type 2 diabetes (T2D), arterial hypertension, dyslipidemia, and coronary heart disease. We identified rare missense mutations (p.Pro191Leu/rs143150225 and p.Ala252Val/rs147624636) in two heterozygous cases. The two CD36 mutation carriers had no family history of T2D and no clustering of cardio-metabolic complications. While the p.Pro191Leu mutation was found in 84 heterozygous carriers from five ethnic groups from the genome aggregation database (global frequency: 0.0297%, N = 141,321), only one European carrier of the p.Ala252Val mutation was identified (global frequency: 0.00040%, N = 125,523). The Pro191 and Ala252 amino acids were not conserved (74.8% and 68.9% across 131 animal species, respectively). In vitro experiments showed that the two CD36 mutant proteins are expressed and trafficked to the plasma membrane where they bind modified low-density-lipoprotein (LDL) cholesterol as normal. However, molecular modelling of the recent CD36 crystal structure showed that Pro191 was located at the exit/entrance gate of the lipid binding chamber and Ala252 was in line with the chamber. Overall, our data do not support a major contribution of CD36 rare coding mutations to T2D and its cardio-metabolic complications in the French population.

Authors: Meyre D; Choquet H; Linton KJ; et al.

Sci Rep. 2019 11 20;9(1):17123. Epub 2019-11-20.

PubMed abstract

Maternal cortisol during pregnancy and offspring schizophrenia: Influence of fetal sex and timing of exposure

Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype-decreased fetal growth-previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings. Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review. Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring. Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.

Authors: Ellman LM; Murphy SK; Maxwell SD; Calvo EM; Cooper T; Schaefer CA; Bresnahan MA; Susser ES; Brown AS

Schizophr Res. 2019 11;213:15-22. Epub 2019-07-22.

PubMed abstract

Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system

To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

Authors: Fohner AE; Ranatunga DK; Thai KK; Lawson BL; Risch N; Oni-Orisan A; Jelalian AT; Rettie AE; Liu VX; Schaefer CA

Pharmacogenet Genomics. 2019 10;29(8):192-199.

PubMed abstract

Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

Authors: Emami NC; Van Den Eeden SK; Witte JS; et al.

Nat Commun. 2019 07 15;10(1):3107. Epub 2019-07-15.

PubMed abstract

Multiple Stakeholder Views on Data Sharing in a Biobank in an Integrated Healthcare Delivery System: Implications for Biobank Governance

Beginning in 2005, researchers at Kaiser Permanente Northern California (KPNC) Division of Research developed the Research Program on Genes, Environment, and Health (RPGEH), a research resource of linked biospecimens, health surveys, and electronic health records on more than 200,000 adult KPNC members. This study examined multiple stakeholders’ values and preferences regarding protection of participants’ privacy and wide sharing of participant data by RPGEH. We conducted 45 semi-structured interviews in person or via phone and two focus groups with seven stakeholder groups, including RPGEH participants and decliners who are KPNC members, KPNC research scientists, external scientists, leadership, Human Subjects Research Protection Program staff, and RPGEH Community Advisory Panel members. Three major themes emerged related to: (1) perceived individual and social harms associated with data sharing; (2) concerns to address when governing access to RPGEH data; and (3) impact of a blurred boundary between research and clinical care in the context of biobanking. The study results were considered in the development of RPGEH data governance and motivated the inclusion of KPNC Community Advisory Panel members and ELSI experts on committees that evaluate data access proposals. Our findings can help inform other biobanks going through similar processes developing data sharing and access policies.

Authors: Tai CG; Harris-Wai J; Schaefer C; Liljestrand P; Somkin CP

Public Health Genomics. 2019 Jun 05:1-10.

PubMed abstract

Telomere length and socioeconomic status at neighborhood and individual levels among 80,000 adults in the Genetic Epidemiology Research on Adult Health and Aging cohort

Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL. The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log2 transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL. Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex. We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.

Authors: Alexeeff, Stacey E; Schaefer, Catherine A; Risch, Neil; Sakoda, Lori C; Quesenberry, Charles P; Van Den Eeden, Stephen K; et al.

Environ Epidemiol. 2019 Jun;3(3):e049. Epub 2019-05-01.

PubMed abstract

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS

Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis. GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

Authors: Rhead B; Schaefer C; Barcellos LF; US Network of Pediatric MS Centers; et al.

Ann Clin Transl Neurol. 2019 Jun;6(6):1053-1061. Epub 2019-05-15.

PubMed abstract

Reproductive Factors and Mammographic Density: Associations Among 24,840 Women and Comparison of Studies Using Digitized Film-Screen Mammography and Full-Field Digital Mammography

Breast density is a modifiable factor that is strongly associated with breast cancer risk. We sought to understand the influence of newer technologies of full-field digital mammography (FFDM) on breast density research and to determine whether results are comparable across studies using FFDM and previous studies using traditional film-screen mammography. We studied 24,840 screening-age (40-74 years) non-Hispanic white women who were participants in the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California and underwent screening mammography with either Hologic (Hologic, Inc., Marlborough, Massachusetts) or General Electric (General Electric Company, Boston, Massachusetts) FFDM machines between 2003 and 2013. We estimated the associations of parity, age at first birth, age at menarche, and menopausal status with percent density and dense area as measured by a single radiological technologist using Cumulus software (Canto Software, Inc., San Francisco, California). We found that associations between reproductive factors and mammographic density measured using processed FFDM images were generally similar in magnitude and direction to those from prior studies using film mammography. Estimated associations for both types of FFDM machines were in the same direction. There was some evidence of heterogeneity in the magnitude of the effect sizes by machine type, which we accounted for using random-effects meta-analysis when combining results. Our findings demonstrate the robustness of quantitative mammographic density measurements across FFDM and film mammography platforms.

Authors: Alexeeff SE; Habel LA; et al.

Am J Epidemiol. 2019 06 01;188(6):1144-1154.

PubMed abstract

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

Authors: Liu M; Choquet H; Weisner C; Vrieze S; et al.

Nat Genet. 2019 02;51(2):237-244. Epub 2019-01-14.

PubMed abstract

Genetic risk factors for pediatric-onset multiple sclerosis

Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10-16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10-16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02. Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.

Authors: Gianfrancesco MA; Schaefer C; Barcellos LF; Network of Pediatric Multiple Sclerosis Centers; et al.

Mult Scler. 2018 12;24(14):1825-1834. Epub 2017-10-05.

PubMed abstract

A Large Multi-ethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci

Body mass index (BMI), a proxy measure for obesity, is determined by both environmental (including ethnicity, age, and sex) and genetic factors, with > 400 BMI-associated loci identified to date. However, the impact, interplay, and underlying biological mechanisms among BMI, environment, genetics, and ancestry are not completely understood. To further examine these relationships, we utilized 427,509 calendar year-averaged BMI measurements from 100,418 adults from the single large multiethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We observed substantial independent ancestry and nationality differences, including ancestry principal component interactions and nonlinear effects. To increase the list of BMI-associated variants before assessing other differences, we conducted a genome-wide association study (GWAS) in GERA, with replication in the Genetic Investigation of Anthropomorphic Traits (GIANT) consortium combined with the UK Biobank (UKB), followed by GWAS in GERA combined with GIANT, with replication in the UKB. We discovered 30 novel independent BMI loci (P < 5.0 × 10-8) that replicated. We then assessed the proportion of BMI variance explained by sex in the UKB using previously identified loci compared to previously and newly identified loci and found slight increases: from 3.0 to 3.3% for males and from 2.7 to 3.0% for females. Further, the variance explained by previously and newly identified variants decreased with increasing age in the GERA and UKB cohorts, echoed in the variance explained by the entire genome, which also showed gene-age interaction effects. Finally, we conducted a tissue expression QTL enrichment analysis, which revealed that GWAS BMI-associated variants were enriched in the cerebellum, consistent with prior work in humans and mice.

Authors: Hoffmann TJ; Choquet H; Yin J; Banda Y; Kvale MN; Glymour M; Schaefer C; Risch N; Jorgenson E

Genetics. 2018 10;210(2):499-515. Epub 2018-08-14.

PubMed abstract

Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort

Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users. We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined. Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P

Authors: Oni-Orisan A; Hoffmann TJ; Ranatunga D; Medina MW; Jorgenson E; Schaefer C; Krauss RM; Iribarren C; Risch N

Circ Genom Precis Med. 2018 Sep;11(9):e002043.

PubMed abstract

Incorporating machine learning approaches to assess putative environmental risk factors for multiple sclerosis

Multiple sclerosis (MS) incidence has increased recently, particularly in women, suggesting a possible role of one or more environmental exposures in MS risk. The study objective was to determine if animal, dietary, recreational, or occupational exposures are associated with MS risk. Least absolute shrinkage and selection operator (LASSO) regression was used to identify a subset of exposures with potential relevance to disease in a large population-based (Kaiser Permanente Northern California [KPNC]) case-control study. Variables with non-zero coefficients were analyzed in matched conditional logistic regression analyses, adjusted for established environmental risk factors and socioeconomic status (if relevant in univariate screening),± genetic risk factors, in the KPNC cohort and, for purposes of replication, separately in the Swedish Epidemiological Investigation of MS cohort. These variables were also assessed in models stratified by HLA-DRB1*15:01 status since interactions between risk factors and that haplotype have been described. There was a suggestive association of pesticide exposure with having MS among men, but only in those who were positive for HLA-DRB1*15:01 (OR pooled = 3.11, 95% CI 0.87, 11.16, p = 0.08). While this finding requires confirmation, it is interesting given the association between pesticide exposure and other neurological diseases. The study also demonstrates the application of LASSO to identify environmental exposures with reduced multiple statistical testing penalty. Machine learning approaches may be useful for future investigations of concomitant MS risk or prognostic factors.

Authors: Mowry EM; Hedström AK; Gianfrancesco MA; Shao X; Schaefer CA; Shen L; Bellesis KH; Briggs FBS; Olsson T; Alfredsson L; Barcellos LF

Mult Scler Relat Disord. 2018 Aug;24:135-141. Epub 2018-06-23.

PubMed abstract

Common mitochondrial haplogroups and cutaneous squamous cell carcinoma risk

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in United States, and its incidence is substantially higher in men than women, but the reasons for the difference are unknown. We explored whether common mitochondrial DNA (mtDNA) haplogroups, which have been associated with cancer risk, and in particular squamous cell carcinoma risk arising in other organs, could explain this biological sex difference in cSCC susceptibility.Methods: We performed a retrospective cohort study using data from the Genetic Epidemiology Research in Adult Health and Aging cohort composed of 67,868 non-Hispanic white subjects (7,701 cSCC cases and 60,167 controls). Genotype information on >665,000 SNPs was generated using Affymetrix Axiom arrays designed to maximize genome-wide coverage, and 102 high-quality mtDNA SNPs were used to determine mtDNA haplogroups. Associations between each mtDNA haplogroup and cSCC risk were evaluated by logistic regression analysis adjusting for age, sex, and population stratification using ancestry principal components.Results: cSCC was more common in men (15.4% vs. 8.4% for women). Nine common mtDNA haplogroups (frequency ≥1%) were identified in addition to the most common haplogroup, H, used as the reference group. No association with cSCC risk was detected for any of the mtDNA haplogroups or overall or sex-stratified analyses.Conclusions: Common mitochondrial variation is not associated with cSCC risk.Impact: This well-powered study refutes the hypothesis that common mitochondrial haplogroups play a role in the differential sex predilection of cSCCs. Cancer Epidemiol Biomarkers Prev; 27(7); 838-41. ©2018 AACR.

Authors: Jorgenson E; Choquet H; Yin J; Asgari MM

Cancer Epidemiol Biomarkers Prev. 2018 07;27(7):838-841. Epub 2018-04-25.

PubMed abstract

A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10-8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.

Authors: Choquet H; Schaefer C; Risch N; Jorgenson E; et al.

Nat Commun. 2018 06 11;9(1):2278. Epub 2018-06-11.

PubMed abstract

Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma

The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated. Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes. Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR = 1.20, p = 9.88 × 10- 11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR = 1.17, p = 2.48 × 10- 10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR = 1.14, p = 2.34 × 10- 9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR = 1.18, p = 5.86 × 10- 10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions. Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

Authors: Wang W; Ollila HM; Whittemore AS; Demehri S; Ioannidis NM; Jorgenson E; Mignot E; Asgari MM

Cancer Immunol Immunother. 2018 May 12.

PubMed abstract

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Authors: Wray NR; Schaefer C; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; et al.

Nat Genet. 2018 05;50(5):668-681. Epub 2018-04-26.

PubMed abstract

Two Genetic Variants Associated with Plantar Fascial Disorders

Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10-8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.

Authors: Kim SK; Ioannidis JPA; Ahmed MA; Avins AL; Kleimeyer JP; Fredericson M; Dragoo JL

Int J Sports Med. 2018 Apr;39(4):314-321. Epub 2018-03-13.

PubMed abstract

A large electronic-health-record-based genome-wide study of serum lipids

A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.

Authors: Hoffmann TJ; Schaefer C; Iribarren C; Risch N; et al.

Nat Genet. 2018 03;50(3):401-413. Epub 2018-03-05.

PubMed abstract

Remote assessment of verbal memory in MS patients using the California Verbal Learning Test

We used the California Verbal Learning Test, Second Edition (CVLT-II), one component of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), to determine feasibility of a remote assessment protocol. We compared telephone-administered CVLT-II data from MS patients to data acquired in person from an independent sample of patients and healthy controls. Mixed factor analyses of variance (ANOVAs) showed no significant differences between patient groups, but between-group effects comparing patients and healthy controls were significant. In this study, CVLT-II assessment by conventional in-person and remote telephone assessment yielded indistinguishable results. The findings indicate that telephone-administered CVLT-II is feasible. Further validation studies are underway.

Authors: Barcellos LF; Bellesis KH; Shen L; Shao X; Chinn T; Frndak S; Drake A; Bakshi N; Marcus J; Schaefer C; Benedict RH

Mult Scler. 2018 03;24(3):354-357. Epub 2017-02-01.

PubMed abstract

A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a leading cause of blindness. IOP heritability has been estimated to up to 67%, and to date only 11 IOP loci have been reported, accounting for 1.5% of IOP variability. Here, we conduct a genome-wide association study of IOP in 69,756 untreated individuals of European, Latino, Asian, and African ancestry. Multiple longitudinal IOP measurements were collected through electronic health records and, in total, 356,987 measurements were included. We identify 47 genome-wide significant IOP-associated loci (P < 5 × 10-8); of the 40 novel loci, 14 replicate at Bonferroni significance in an external genome-wide association study analysis of 37,930 individuals of European and Asian descent. We further examine their effect on the risk of glaucoma within our discovery sample. Using longitudinal IOP measurements from electronic health records improves our power to identify new variants, which together explain 3.7% of IOP variation.

Authors: Choquet H; Thai KK; Yin J; Hoffmann TJ; Kvale MN; Banda Y; Schaefer C; Risch N; Nair KS; Melles R; Jorgenson E

Nat Commun. 2017 Dec 13;8(1):2108. Epub 2017-12-13.

PubMed abstract

Genome-wide association study identifies a locus associated with rotator cuff injury

Rotator cuff tears are common, especially in the fifth and sixth decades of life, but can also occur in the competitive athlete. Genetic differences may contribute to overall injury risk. Identifying genetic loci associated with rotator cuff injury could shed light on the etiology of this injury. We performed a genome-wide association screen using publically available data from the Research Program in Genes, Environment and Health including 8,357 cases of rotator cuff injury and 94,622 controls. We found rs71404070 to show a genome-wide significant association with rotator cuff injury with p = 2.31×10-8 and an odds ratio of 1.25 per allele. This SNP is located next to cadherin8, which encodes a protein involved in cell adhesion. We also attempted to validate previous gene association studies that had reported a total of 18 SNPs showing a significant association with rotator cuff injury. However, none of the 18 SNPs were validated in our dataset. rs71404070 may be informative in explaining why some individuals are more susceptible to rotator cuff injury than others.

Authors: Roos TR; Roos AK; Avins AL; Ahmed MA; Kleimeyer JP; Fredericson M; Ioannidis JPA; Dragoo JL; Kim SK

PLoS ONE. 2017;12(12):e0189317. Epub 2017-12-11.

PubMed abstract

A Genetic Marker Associated with De Quervain’s Tenosynovitis

De Quervain’s tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain’s tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain’s tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain’s tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.

Authors: Kim SK; Ahmed MA; Avins AL; Ioannidis JPA

Int J Sports Med. 2017 Nov;38(12):942-948. Epub 2017-10-06.

PubMed abstract

The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement

Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

Authors: Hedström AK; Schaefer CA; Alfredsson L; et al.

Eur J Epidemiol. 2017 Oct;32(10):909-919. Epub 2017-06-08.

PubMed abstract

Two genetic loci associated with ankle injury

Ankle injuries, including sprains, strains and other joint derangements and instability, are common, especially for athletes involved in indoor court or jumping sports. Identifying genetic loci associated with these ankle injuries could shed light on their etiologies. A genome-wide association screen was performed using publicly available data from the Research Program in Genes, Environment and Health (RPGEH) including 1,694 cases of ankle injury and 97,646 controls. An indel (chr21:47156779:D) that lies close to a collagen gene, COL18A1, showed an association with ankle injury at genome-wide significance (p = 3.8×10-8; OR = 1.99; 95% CI = 1.75-2.23). A second DNA variant (rs13286037 on chromosome 9) that lies within an intron of the transcription factor gene NFIB showed an association that was nearly genome-wide significant (p = 5.1×10-8; OR = 1.63; 95% CI = 1.46-1.80). The ACTN3 R577X mutation was previously reported to show an association with acute ankle sprains, but did not show an association in this cohort. This study is the first genome-wide screen for ankle injury that yields insights regarding the genetic etiology of ankle injuries and provides DNA markers with the potential to inform athletes about their genetic risk for ankle injury.

Authors: Kim SK; Kleimeyer JP; Ahmed MA; Avins AL; Fredericson M; Dragoo JL; Ioannidis JPA

PLoS ONE. 2017;12(9):e0185355. Epub 2017-09-28.

PubMed abstract

Age at menarche and late adolescent adiposity associated with mammographic density on processed digital mammograms in 24,840 women

Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density.Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders.Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend <0.0001) and DA (P value for trend <0.0001) in fully adjusted models. Compared with the reference category of ages 12 to 13 years at menarche, menarche at age >16 years was associated with an increase in PD of 1.47% (95% CI, 0.69-2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48-2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models.Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images.Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. Cancer Epidemiol Biomarkers Prev; 26(9); 1450-8. ©2017 AACR.

Authors: Alexeeff SE; Habel LA; et al.

Cancer Epidemiol Biomarkers Prev. 2017 Sep;26(9):1450-1458. Epub 2017-07-11.

PubMed abstract

Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects’ alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10-72) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10-4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10-20for drinker status and beta=-0.19, P=1.91 × 10-35for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10-7and beta=-0.21, P=2.58 × 10-6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10-10for drinks/week and OR=0.96, P=4.08 × 10-5for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10-8for drinks/week and OR=1.04, P=5 × 10-4for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Authors: Jorgenson E; Thai KK; Hoffmann TJ; Sakoda LC; Kvale MN; Banda Y; Schaefer C; Risch N; Mertens J; Weisner C; Choquet H

Mol Psychiatry. 2017 Sep;22(9):1359-1367. Epub 2017-05-09.

PubMed abstract

Two Genetic Loci associated with Medial Collateral Ligament Injury

Medial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10-8) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

Authors: Roos AK; Avins AL; Ahmed MA; Kleimeyer JP; Roos TR; Fredericson M; Ioannidis JPA; Dragoo JL; Kim S

Int J Sports Med. 2017 Jul;38(7):501-507. Epub 2017-05-08.

PubMed abstract

A Genetic Marker Associated with Shoulder Dislocation

Shoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10-9; odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.

Authors: Kim S; Kleimeyer JP; Ahmed MA; Avins AL; Fredericson M; Dragoo JL; Ioannidis JPA

Int J Sports Med. 2017 Jul;38(7):508-514. Epub 2017-05-18.

PubMed abstract

Maternal serum cytokine levels and risk of bipolar disorder

Prenatal exposure to influenza has previously been associated with increased risk of bipolar disorder (BD), an association that may be mediated by maternal cytokines. The objective of this study was to determine the association between maternal levels of cytokines measured during each trimester of pregnancy and the risk of BD in offspring. We conducted a case-control study nested in the Child Health and Development Study, a birth cohort that enrolled pregnant women in 1959-1966. Potential cases with DSM-IV-TR bipolar I disorder, bipolar II disorder, BD not otherwise specified, and BD with psychotic features were ascertained through electronic medical records, a public agency database, and a mailing to the cohort. Diagnoses were confirmed by clinical interview. Nine cytokines (IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, TNF-α and GM-CSF) were measured simultaneously by Luminex assays in archived prenatal maternal serum samples from 85 cases and 170 matched controls. Data were analyzed using conditional logistic regression. In the overall study sample, there were no significant associations between prenatal maternal cytokine levels and BD after adjustment for confounders. The risk of BD without psychotic features was decreased among subjects with higher maternal levels of first trimester log-transformed IL-4 (OR (95% CI)=0.76 (0.58, 0.98); p=0.04) and third trimester log-transformed IL-6 (OR (95% CI)=0.64 (0.42, 0.98); p=0.04). In conclusion, higher levels of prenatal maternal cytokines were not associated with increased risk for BD. Further studies with larger samples are necessary to confirm the finding.

Authors: Cheslack-Postava K; Cremers S; Bao Y; Shen L; Schaefer CA; Brown AS

Brain Behav Immun. 2017 Jul;63:108-114. Epub 2016-07-29.

PubMed abstract

Variants in Pharmacokinetic Transporters and Glycaemic Response to Metformin: A MetGen Meta-Analysis

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Authors: Dujic T; van der Heijden AA; Pearson ER; et al.

Clin Pharmacol Ther. 2017 Jun;101(6):763-772. Epub 2017-02-03.

PubMed abstract

Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

Authors: Gianfrancesco MA; Barcellos LF; Waubant E; Network of Pediatric Multiple Sclerosis Centers; et al.

Neurology. 2017 Apr 25;88(17):1623-1629. Epub 2017-03-29.

PubMed abstract

Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

Authors: Gianfrancesco MA; Schaefer C; Barcellos LF; et al.

Am J Epidemiol. 2017 02 01;185(3):162-171.

PubMed abstract

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Authors: Hoffmann TJ; Sakoda LC; Habel LA; Quesenberry CP; Schaefer C; Risch N; Van Den Eeden SK; Witte JS; et al.

Nat Commun. 2017 Jan 31;8:14248. Epub 2017-01-31.

PubMed abstract

Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men

Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin. Statistical analyses of individual participant data from 12,330 male controls aged 25-85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates. Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones. Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.

Authors: Watts EL; Habel LA; Schaefer CA; Travis RC; et al.

PLoS ONE. 2017;12(12):e0187741. Epub 2017-12-27.

PubMed abstract

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease

The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Authors: Brant SR; Klapproth JA; Kugathasan S; et al.

Gastroenterology. 2017 01;152(1):206-217.e2. Epub 2016-09-28.

PubMed abstract

Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy

Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries.

Authors: Kim SK; Roos TR; Roos AK; Kleimeyer JP; Ahmed MA; Goodlin GT; Fredericson M; Ioannidis JP; Avins AL; Dragoo JL

PLoS ONE. 2017;12(3):e0170422. Epub 2017-03-30.

PubMed abstract

Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation

Longitudinal electronic health records on 99,785 Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort individuals provided 1,342,814 systolic and diastolic blood pressure measurements for a genome-wide association study on long-term average systolic, diastolic, and pulse pressure. We identified 39 new loci among 75 genome-wide significant loci (P ≤ 5 × 10(-8)), with most replicating in the combined International Consortium for Blood Pressure (ICBP; n = 69,396) and UK Biobank (UKB; n = 152,081) studies. Combining GERA with ICBP yielded 36 additional new loci, with most replicating in UKB. Combining all three studies (n = 321,262) yielded 241 additional genome-wide significant loci, although no replication sample was available for these. All associated loci explained 2.9%, 2.5%, and 3.1% of variation in systolic, diastolic, and pulse pressure, respectively, in GERA non-Hispanic whites. Using multiple blood pressure measurements in GERA doubled the variance explained. A normalized risk score was associated with time to onset of hypertension (hazards ratio = 1.18, P = 8.2 × 10(-45)). Expression quantitative trait locus analysis of blood pressure loci showed enrichment in aorta and tibial artery.

Authors: Hoffmann TJ; Ehret GB; Nandakumar P; Ranatunga D; Schaefer C; Kwok PY; Iribarren C; Chakravarti A; Risch N

Nat Genet. 2017 Jan;49(1):54-64. Epub 2016-11-14.

PubMed abstract

Clinical Utility of Multi-marker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study among over 51 Thousand Individuals of European Ancestry

We evaluated whether including multilocus genetic risk scores (GRSs) into the Framingham Risk Equation improves the predictive capacity, discrimination, and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. We performed a cohort study among 51 954 European-ancestry members of a Northern California integrated healthcare system (67% female; mean age 59) free of CHD at baseline (2007-2008). Four GRSs were constructed using between 8 and 51 previously identified genetic variants. After a mean (±SD) follow-up of 5.9 (±1.5) years, 1864 incident CHD events were documented. All GRSs were linearly associated with CHD in a model adjusted by individual risk factors: hazard ratio (95% confidence interval) per SD unit: 1.21 (1.15-1.26) for GRS_8, 1.20 (1.15-1.26) for GRS_12, 1.23 (1.17-1.28) for GRS_36, and 1.23 (1.17-1.28) for GRS_51. Inclusion of the GRSs improved the C statistic (ΔC statistic =0.008 for GRS_8 and GRS_36; 0.007 for GRS_12; and 0.009 for GRS_51; all P<0.001). The net reclassification improvement was 5% for GRS_8, GRS_12, and GRS_36 and 4% for GRS_51 in the entire cohort and was (after correcting for bias) 9% for GRS_8 and GRS_12 and 7% for GRS_36 and GRS_51 when analyzing those classified as intermediate Framingham risk (10%-20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS_8 and GRS_12, 41 for GRS_36, and 43 for GRS_51. Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of 4 multilocus GRSs for incident CHD among subjects of European ancestry.

Authors: Iribarren C; Lu M; Jorgenson E; Martínez M; Lluis-Ganella C; Subirana I; Salas E; Elosua R

Circ Cardiovasc Genet. 2016 Dec;9(6):531-540. Epub 2016-10-25.

PubMed abstract

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Authors: Barban N; Guo X; Mills MC; et al.

Nat Genet. 2016 Dec;48(12):1462-1472. Epub 2016-10-31.

PubMed abstract

The Kaiser Permanente Northern California research program on genes, environment, and health (RPGEH) pregnancy cohort: study design, methodology and baseline characteristics

Exposures during the prenatal period may have lasting effects on maternal and child health outcomes. To better understand the effects of the in utero environment on children’s short- and long-term health, large representative pregnancy cohorts with comprehensive information on a broad range of environmental influences (including biological and behavioral) and the ability to link to prenatal, child and maternal health outcomes are needed. The Research Program on Genes, Environment and Health (RPGEH) pregnancy cohort at Kaiser Permanente Northern California (KPNC) was established to create a resource for conducting research to better understand factors influencing women’s and children’s health. Recruitment is integrated into routine clinical prenatal care at KPNC, an integrated health care delivery system. We detail the study design, data collection, and methodologies for establishing this cohort. We also describe the baseline characteristics and the cohort’s representativeness of the underlying pregnant population in KPNC. While recruitment is ongoing, as of October 2014, the RPGEH pregnancy cohort included 16,977 pregnancies (53 % from racial and ethnic minorities). RPGEH pregnancy cohort participants consented to have blood samples obtained in the first trimester (mean gestational age 9.1 weeks ± 4.2 SD) and second trimester (mean gestational age 18.1 weeks ± 5.5 SD) to be stored for future use. Women were invited to complete a questionnaire on health history and lifestyle. Information on women’s clinical and health assessments before, during and after pregnancy and women and children’s health outcomes are available in the health system’s electronic health records, which also allows long-term follow-up. This large, racially- and ethnically-diverse cohort of pregnancies with prenatal biospecimens and clinical data is a valuable resource for future studies on in utero environmental exposures and maternal and child perinatal and long term health outcomes. The baseline characteristics of RPGEH Pregnancy Cohort demonstrate that it is highly representative of the underlying population living in the broader community in Northern California.

Authors: Hedderson MM; Ferrara A; Avalos LA; Van den Eeden SK; Gunderson EP; Li DK; Schaefer C; Croen LA; et al.

BMC Pregnancy Childbirth. 2016 Nov 29;16(1):381. Epub 2016-11-29.

PubMed abstract

A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin

One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

Authors: Goswami S; Hedderson MM; Savic RM; et al.

Clin Pharmacol Ther. 2016 Nov;100(5):537-547. Epub 2016-09-23.

PubMed abstract

A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0×10-11), 52Kb 3′ of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8×10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9×10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2×10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.

Authors: Hoffmann TJ; Keats BJ; Yoshikawa N; Schaefer C; Risch N; Lustig LR

PLoS Genet. 2016 Oct;12(10):e1006371. Epub 2016-10-20.

PubMed abstract

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk

We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality. We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles. Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity. These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.

Authors: Rhead B; Schaefer C; Barcellos LF; et al.

Neurol Genet. 2016 Oct;2(5):e97. Epub 2016-09-13.

PubMed abstract

Maternal T. gondii, offspring bipolar disorder and neurocognition

Prenatal exposure to maternal Toxoplasma gondii (T. gondii) IgG antibody titer has been associated previously with an increased risk of offspring schizophrenia (SZ) and cognitive impairment. We examined maternal T. gondii, offspring bipolar disorder (BP) and childhood cognition using a population-based birth cohort. Maternal sera, drawn in the third trimester, were analyzed for T. gondii IgG antibody titer, and offspring cognition at ages 5 and 9-11 was measured with the Peabody Picture Vocabulary Test (PPVT) and the Raven Matrices (Raven). Raw scores were standardized and the ages combined. Potential cases with BP from the cohort were identified by database linkages. This protocol identified 85 cases who were matched 1:2 to controls. Maternal T. gondii IgG was not associated with the risk of BP in offspring. Neither moderate [HR=1.43 (CI: 0.49, 4.17)] nor high IgG titer [HR=1.6 [CI: 0.74, 3.48)] were associated with offspring BP. Associations were not observed between maternal T. gondii and BP with psychotic features or BP type 1. In addition, maternal T. gondii was not associated with childhood cognition. Our study suggests that T. gondii may be specific to SZ among major psychotic disorders, though further studies with larger sample sizes are required.

Authors: Freedman D; Bao Y; Shen L; Schaefer CA; Brown AS

Psychiatry Res. 2016 Sep 30;243:382-9. Epub 2016-07-07.

PubMed abstract

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Authors: Zhou K; Hedderson MM; Pearson ER; et al.

Nat Genet. 2016 Sep;48(9):1055-1059. Epub 2016-08-08.

PubMed abstract

The Association of Refractive Error with Glaucoma in a Multiethnic Population

To evaluate the association between refractive error and the prevalence of glaucoma by race or ethnicity. Cross-sectional study. Kaiser Permanente Northern California Health Plan members with refractive error measured at 35 years of age or older between 2008 and 2014 and with no history of cataract surgery, refractive surgery, or a corneal disorder. We identified 34 040 members with glaucoma or ocular hypertension (OHTN; cases) and 403 398 members without glaucoma (controls). Glaucoma cases were classified as primary angle-closure glaucoma (PACG); 1 of the 4 forms of open-angle glaucoma: primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), pigmentary glaucoma (PIGM), and pseudoexfoliation glaucoma (PEX); or OHTN. Refractive error, expressed as spherical equivalent (SE), was coded as a continuous trait and also as categories. Logistic regression analyses were used to estimate the association between refractive error and the prevalence of glaucoma overall and in specific racial or ethnic groups. The association between refractive error and glaucoma subtypes evaluated as odds ratios (ORs) with 95% confidence intervals (CIs). In controls, the mean SE was -0.59 diopters (D) (standard deviation, 2.62 D). Each 1-D reduction in SE was associated with a 22% decrease in the odds of PACG (OR, 0.78; 95% CI, 0.77-0.80) and with increases in the odds of open-angle glaucoma ranging from 1.23 (95% CI, 1.20-1.26) for PIGM, to 1.07 (95% CI, 1.03-1.11) for PEX, and to 1.05 (95% CI, 1.04-1.06) for OHTN. In addition, we observed a stronger association between myopia and POAG among non-Hispanic whites (OR, 1.12; 95% CI, 1.11-1.13) and NTG among Asians (OR, 1.17; 95% CI, 1.15-1.20) and non-Hispanic whites (OR, 1.19; 95% CI, 1.15-1.22). Myopia was associated with an increased prevalence of all forms of open-angle glaucoma and OHTN, whereas hyperopia was associated with a substantially increased prevalence of PACG. Although high myopia is a strong risk factor for glaucoma subtypes, low and moderate myopia also have a significant effect on glaucoma risk. Additionally, there were moderate racial differences in the association of myopia with the risk of POAG and NTG.

Authors: Shen L; Melles RB; Metlapally R; Barcellos L; Schaefer C; Risch N; Herrinton LJ; Wildsoet C; Jorgenson E

Ophthalmology. 2015 Aug 7.

PubMed abstract

Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies

We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS). Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded Disability Status Scale at study entry and disease duration. MSSS was considered as a continuous variable and as 2 dichotomous variables (median and extreme ends; MSSS of ?5 vs >5 and MSSS of <2.5 vs ?7.5, respectively). Single nucleotide polymorphisms (SNPs) were examined individually and as both combined weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) for association with disease severity. Random-effects meta-analyses were conducted and adjusted for cohort, sex, age at onset, and HLA-DRB1*15:01. A total of 7,125 MS cases were analyzed. The wGRS and GRS were not strongly associated with disease severity after accounting for cohort, sex, age at onset, and HLA-DRB1*15:01. After restricting analyses to cases with disease duration ?10 years, associations were null (p value ?0.05). No SNP was associated with disease severity after adjusting for multiple testing. The largest meta-analysis of established MS genetic risk variants and disease severity, to date, was performed. Results suggest that the investigated MS genetic risk variants are not associated with MSSS, even after controlling for potential confounders. Further research in large cohorts is needed to identify genetic determinants of disease severity using sensitive clinical and MRI measures, which are critical to understanding disease mechanisms and guiding development of effective treatments.

Authors: George MF; Schaefer C; Barcellos LF; et al.

Neurol Genet. 2016 Aug;2(4):e87. Epub 2016-08-04.

PubMed abstract

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD.

Authors: Jorgenson E; Melles RB; Hoffmann TJ; Jia X; Sakoda LC; Kvale MN; Banda Y; Schaefer C; Risch N; Shen L

Eur J Hum Genet. 2016 Jul;24(7):1049-55. Epub 2016-01-06.

PubMed abstract

Case-control study of mammographic density and breast cancer risk using processed digital mammograms

Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care. We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use. Median intra-reader reproducibility was high with a Pearson’s r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm(2) (18.22 cm(2)) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41-2.04) for PD, and 1.54 (1.34-1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91-2.45), 2.57 (1.54-4.30), 3.22 (1.91-5.43), 4.88 (2.78-8.55) for PD, and 1.00 (ref.), 1.43 (0.85-2.40), 2.53 (1.53-4.19), 2.85 (1.73-4.69), 3.48 (2.14-5.65) for DA. PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research.

Authors: Habel LA; Lipson JA; Achacoso N; Rothstein JH; Yaffe MJ; Liang RY; Acton L; McGuire V; Whittemore AS; Rubin DL; Sieh W

Breast Cancer Res. 2016 May 21;18(1):53. Epub 2016-05-21.

PubMed abstract

High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies

Previous studies on consumption of caffeine and risk of multiple sclerosis (MS) have yielded inconclusive results. We aimed to investigate whether consumption of coffee is associated with risk of MS. Using two population-representative case-control studies (a Swedish study comprising 1620 cases and 2788 controls, and a US study comprising 1159 cases and 1172 controls), participants with different habits of coffee consumption based on retrospective data collection were compared regarding risk of MS, by calculating ORs with 95% CIs. Logistic regression models were adjusted for a broad range of potential confounding factors. Compared with those who reported no coffee consumption, the risk of MS was substantially reduced among those who reported a high consumption of coffee exceeding 900 mL daily (OR 0.70 (95% CI 0.49 to 0.99) in the Swedish study, and OR 0.69 (95% CI 0.50 to 0.96) in the US study). Lower odds of MS with increasing consumption of coffee were observed, regardless of whether coffee consumption at disease onset or 5 or 10 years prior to disease onset was considered. In accordance with studies in animal models of MS, high consumption of coffee may decrease the risk of developing MS. Caffeine, one component of coffee, has neuroprotective properties, and has been shown to suppress the production of proinflammatory cytokines, which may be mechanisms underlying the observed association. However, further investigations are needed to determine whether exposure to caffeine underlies the observed association and, if so, to evaluate its mechanisms of action.

Authors: Hedström AK; Mowry EM; Gianfrancesco MA; Shao X; Schaefer CA; Shen L; Olsson T; Barcellos LF; Alfredsson L

J Neurol Neurosurg Psychiatr. 2016 May;87(5):454-60. Epub 2016-03-03.

PubMed abstract

Identification of Susceptibility Loci for Cutaneous Squamous Cell Carcinoma

We report a genome-wide association study of cutaneous squamous cell carcinoma conducted among non-Hispanic white members of the Kaiser Permanente Northern California health care system. The study includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5,600 controls). Combined analysis of screening and replication phases identified 10 loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5 × 10(-8). Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate squamous cell carcinoma risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated squamous cell carcinoma risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited squamous cell carcinoma susceptibility.

Authors: Asgari MM; Wang W; Ioannidis NM; Itnyre J; Hoffmann T; Jorgenson E; Whittemore AS

J Invest Dermatol. 2016 May;136(5):930-7. Epub 2016-01-29.

PubMed abstract

A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ? 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.

Authors: Travis RC; Hamdy FC; Schenk JM; Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group; et al.

Cancer Res. 2016 04 15;76(8):2288-300. Epub 2016-02-26.

PubMed abstract

Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1

​BACKGROUND:Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.METHODS:Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 ‘common Hispanic mutation’ (CCM1-CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.RESULTS:The CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.CONCLUSIONS:Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.

Authors: Choquet H; Trapani E; Goitre L; Trabalzini L; Akers A; Fontanella M; Hart BL; Morrison LA; Pawlikowska L; Kim H; Retta SF

Free Radic Biol Med. 2016 Mar;92:100-9. doi: 10.1016/j.freeradbiomed.2016.01.008. Epub 2016 Jan 19.

PubMed abstract

Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: Differential influences of fetal sex

Exposure to adverse life events during pregnancy has been linked to increased risk of schizophrenia spectrum disorders (SSD) in offspring. Nevertheless, much of the previous work inferred maternal stress from severe life events rather than directly assessing maternal reports of stress. The present study aimed to examine maternal reports of stress during pregnancy and risk for offspring SSD. Participants were 95 SSD cases and 206 controls who were offspring from a large birth cohort study that followed pregnant women from 1959 to 1966. During pregnancy interviews, women were asked if anything worrisome had occurred recently. Interviews were qualitatively coded for stress-related themes, including reports of daily life stress, by two independent raters. None of the maternal psychosocial stress themes were significantly associated with increased odds of offspring SSD in analyses of the full sample. However, results indicated a significant daily life stress by infant sex interaction. Maternal daily life stress during pregnancy was associated with significantly increased odds of SSD among male offspring. Findings suggest sex-specific fetal sensitivity to maternal reported daily life stress during pregnancy on risk for SSD, with males appearing to be more vulnerable to the influences of maternal stress during pregnancy.

Authors: Fineberg AM; Ellman LM; Schaefer CA; Maxwell SD; Shen L; H Chaudhury N; Cook AL; Bresnahan MA; Susser ES; Brown AS

Psychiatry Res. 2016 Feb 28;236:91-7. Epub 2015-12-18.

PubMed abstract

Feasibility study for remote assessment of cognitive function in multiple sclerosis

Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published. To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals. The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized. 11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007). Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.

Authors: George MF; Holingue CB; Briggs FB; Shao X; Bellesis KH; Whitmer RA; Schaefer C; Benedict RH; Barcellos LF

J Neurol Neuromedicine. 2016;1(8):10-18.

PubMed abstract

Diabetes Pathology and Risk of Primary Open-Angle Glaucoma: Evaluating Causal Mechanisms by Using Genetic Information

Although type 2 diabetes (T2D) predicts glaucoma, the potential for unmeasured confounding has hampered causal conclusions. We performed separate sample genetic instrumental variable analyses using the Genetic Epidemiology Research Study on Adult Health and Aging cohort (n = 69,685; 1995-2013) to estimate effects of T2D on primary open-angle glaucoma (POAG; 3,554 cases). Genetic instrumental variables for overall and mechanism-specific (i.e., linked to T2D via influences on adiposity, ?-cell function, insulin regulation, or other metabolic processes) T2D risk were constructed by using 39 genetic polymorphisms established to predict T2D in other samples. Instrumental variable estimates indicated that T2D increased POAG risk (odds ratio = 2.53, 95% confidence interval: 1.04, 6.11). The instrumental variable for ?-cell dysregulation also significantly predicted POAG (odds ratio?-cell = 5.26, 95% confidence interval: 1.75, 15.85), even among individuals without diagnosed T2D, suggesting that metabolic dysregulation may increase POAG risk prior to T2D diagnosis. The T2D risk variant in the melatonin receptor 1B gene (MTNR1B) predicted risk of POAG independently of T2D status, indicating possible pleiotropic physiological functions of melatonin, but instrumental variable effect estimates were significant even excluding MTNR1B variants. To our knowledge, this is the first genetic instrumental variable study of T2D and glaucoma, providing a novel approach to evaluating this hypothesized relationship. Our findings substantially bolster observational evidence that T2D increases POAG risk.

Authors: Shen L; Walter S; Melles RB; Glymour MM; Jorgenson E

Am J Epidemiol. 2015 Nov 25.

PubMed abstract

Polymorphisms In HLA Class II Genes Are Associated With Susceptibility To Staphylococcus aureus Infection In A Caucasian Population

Staphylococcus aureus (S. aureus) can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. A genomewide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45344 matched controls; 584,535 single nucleotide polymorphisms (SNP) were genotyped on a European-specific array. Coverage was increased by imputation of >25 million common SNPs using 1000 Genomes Reference panel. In addition human leukocyte antigen (HLA) serotypes were also imputed. ?Logistic regression assuming an additive genetic model revealed several imputed SNPs [e.g., SNP rs115231074: odds ratio (OR)=1.22, P=1.3 x 10(-10); rs35079132: OR=1.24, P=3.8 x 10(-8)] achieving genome-wide significance on chromosome 6 in HLA Class II region. One adjacent genotyped SNP was nearly genomewide significant (rs4321864 OR=1.13, P=8.8 x 10(-8)). These polymorphisms are located near HLA-DRA and HLA-DRB1 genes. Further logistic regression results where the most significant GWAS SNPs were conditioned on HLA-DRB1*04 serotype showed additional support for the strength of association between HLA Class II genetic variants with S. aureus infection. Our study results provide the first reported evidence of human genetic susceptibility to S. aureus infection.

Authors: DeLorenze GN; Nelson CL; Scott WK; Allen AS; Ray GT; Tsai AL; Quesenberry CP; Fowler VG

J Infect Dis. 2015 Oct 8.

PubMed abstract

Genetics of cerebral cavernous malformations: current status and future prospects

​Cerebral cavernous malformations (CCM) are vascular lesions which affect up to 0.5% of the general population, predisposing to headaches, seizures, cerebral hemorrhages and focal neurological deficits. CCM occurs in both sporadic and familial forms; familial cases follow an autosomal-dominant mode of inheritance and are caused by mutations in CCM1 (KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10). Somatic mutations within the three CCM genes have been identified in CCM lesions from both sporadic and familial patients. We reviewed articles published in PubMed in English prior to March 2015 and provide an update on CCM mutations and the screening strategies used to identify them. Further, we summarize the specific clinical features related to CCM genotypes. As 5% to 15% of familial CCM cases remain genetically unexplained, we also discuss future approaches to expand understanding of the genetic architecture of CCM. Finally, we discuss possible genetic modifiers of CCM disease severity and progression. Understanding the genetic architecture of CCM is essential for an earlier diagnosis of the disease, predictive testing of at-risk patients, and design of targeted medical therapies of which there are currently none available.

Authors: Choquet H; Pawlikowska L; Lawton MT; Kim H.

J Neurosurg Sci. 2015 Sep;59(3):211-20. Epub 2015 Apr 22.

PubMed abstract

Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. Principal component (PC) and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed, considering only nonadjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3741 genetically identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to intermarriage. The parent-child pairs revealed a trend toward increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories creates interesting challenges and future opportunities for genetic epidemiologic studies.

Authors: Banda Y; Croen LA; Iribarren C; Kushi LH; Quesenberry CP; Sakoda LC; Van Den Eeden SK; Whitmer RA; Schaefer C; Risch N; et al.

Genetics. 2015 Aug;200(4):1285-95. Epub 2015-06-19.

PubMed abstract

Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.

Authors: Lapham K; Croen LA; Iribarren C; Kushi LH; Quesenberry CP; Sakoda LC; Van Den Eeden SK; Whitmer RA; Risch N; Schaefer C; Blackburn EH; et al.

Genetics. 2015 Aug;200(4):1061-72. Epub 2015-06-19.

PubMed abstract

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of >100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated >70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions.

Authors: Kvale MN; Croen LA; Iribarren C; Kushi LH; Quesenberry CP; Sakoda LC; Van Den Eeden SK; Whitmer RA; Schaefer C; Risch N; et al.

Genetics. 2015 Aug;200(4):1051-60. Epub 2015-06-19.

PubMed abstract

A large multi-ethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.

Authors: Hoffmann TJ; Van Den Eeden SK; Sakoda LC; Habel LA; Quesenberry CP; Schaefer C; Witte JS; et al.

Cancer Discov. 2015 Aug;5(8):878-91. Epub 2015-06-01.

PubMed abstract

Differences in the Genetic Susceptibility to Age-Related Macular Degeneration Clinical Subtypes

We compared across age-related macular degeneration (AMD) subtypes the effect of AMD risk variants, their predictive power, and heritability. The prevalence of AMD was estimated among active non-Hispanic white Kaiser Permanente Northern California members who were at least 65 years of age as of June 2013. The genetic analysis included 5,170 overall AMD cases ascertained from electronic health records (EHR), including 1,239 choroidal neovascularization (CNV) cases and 1,060 nonexudative AMD cases without CNV, and 23,130 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Imputation was based on the 1000 Genomes Project reference panel. The narrow-sense heritability due to common autosomal single nucleotide polymorphisms (SNPs) was 0.37 for overall AMD, 0.19 for AMD unspecified, 0.20 for nonexudative AMD, and 0.60 for CNV. For the 19 previously reported AMD risk loci, the area under the receiver operating characteristic (ROC) curve was 0.675 for overall AMD, 0.640 for AMD unspecified, 0.678 for nonexudative AMD, and 0.766 for CNV. The individual effects on the risk of AMD for 18 of the 19 SNPs were in a consistent direction with those previously reported, including a protective effect of the APOE ?4 allele. Conversely, the risk of AMD was significantly increased in carriers of the ?2 allele. These findings provide an independent confirmation of many of the previously identified AMD risk loci, and support a potentially greater role of genetic factors in the development of CNV. The replication of established associations validates the use of EHR in genetic studies of ophthalmologic traits.

Authors: Shen L; Hoffmann TJ; Melles RB; Sakoda LC; Kvale MN; Banda Y; Schaefer C; Risch N; Jorgenson E

Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4290-9.

PubMed abstract

Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response

The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente’s Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Authors: Wen CC; Yee SW; Liang X; Hoffmann TJ; Kvale MN; Banda Y; Jorgenson E; Schaefer C; Risch N; Giacomini KM

Clin Pharmacol Ther. 2015 May;97(5):518-25. Epub 2015-04-06.

PubMed abstract

Perinatal oxytocin increases the risk of offspring bipolar disorder and childhood cognitive impairment

We tested the hypothesis that perinatal oxytocin, given to pregnant women to induce labor, is related to offspring bipolar disorder (BP) and worse childhood cognitive performance among offspring. We also tested the association between childhood cognition and later BP. A population-based birth cohort derived from the Child Health and Development Study (CHDS) which included nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) between 1959 and 1966. Prospectively obtained medical and offspring cognitive performance were used. Potential cases with BP from the cohort were identified by database linkages. This protocol identified 94 cases who were matched 1:8 to controls. Perinatal oxytocin was associated with a 2.4 times increased odds of later BP. Oxytocin was also associated with decreased performance on the Raven Matrices, but not on the Peabody Picture Vocabulary Test (PPVT). Childhood cognition was not associated with later BP. Loss to follow-up must be considered in all birth cohort studies. In addition, the childhood cognitive battery did not include tests related to multiple domains of cognition which have been associated with later BP. A third limitation is the modest sample size of those exposed to oxytocin. This study provides evidence for a potentially important perinatal risk factor for BP and cognitive impairment in childhood. While the association between perinatal oxytocin and offspring BP must be viewed cautiously until further studies can attempt to replicate the result, it lends support to the broader view that neurodevelopmental factors contribute to BP.

Authors: Freedman D; Brown AS; Shen L; Schaefer CA

J Affect Disord. 2015 Mar 1;173:65-72. Epub 2014-11-08.

PubMed abstract

A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia

Inguinal hernia repair is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop inguinal hernias. We perform a genome-wide association analysis of surgically confirmed inguinal hernias in 72,805 subjects (5,295 cases and 67,510 controls) and confirm top associations in an independent cohort of 92,444 subjects with self-reported hernia repair surgeries (9,701 cases and 82,743 controls). We identify four novel inguinal hernia susceptibility loci in the regions of EFEMP1, WT1, EBF2 and ADAMTS6. Moreover, we observe expression of all four genes in mouse connective tissue and network analyses show an important role for two of these genes (EFEMP1 and WT1) in connective tissue maintenance/homoeostasis. Our findings provide insight into the aetiology of hernia development and highlight genetic pathways for studies of hernia development and its treatment.

Authors: Jorgenson E; Makki N; Shen L; Chen DC; Tian C; Eckalbar WL; Hinds D; Ahituv N; Avins A

Nat Commun. 2015;6:10130. Epub 2015-12-21.

PubMed abstract

Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort

An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show here that-by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers-we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from the California Men’s Health Study specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37-0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4×10-12). The G84E mutation was also suggestively associated with an increase in risk for the following cancer sites by approximately 50% in a pleiotropic manner: breast, non-Hodgkin’s lymphoma, kidney, bladder, melanoma, endometrium, and pancreas (p = 0.042).

Authors: Hoffmann TJ; Sakoda LC; Habel LA; Asgari MM; Corley D; Kushi LH; Quesenberry CP; Schaefer C; Van Den Eeden SK; Risch N; Witte JS; et al.

PLoS Genet. 2015 Jan;11(1):e1004930. Epub 2015-01-28.

PubMed abstract

Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk

The recently described interaction between smoking, human leukocyte antigen (HLA) DRB1*15 and absence of HLA-A*02 with regard to multiple sclerosis (MS) risk shows that the risk conveyed by smoking differs depending on genetic background. We aimed to investigate whether a similar interaction exists between passive smoking and HLA genotype. We used one case-control study with incident cases of MS (736 cases, 1195 controls) and one with prevalent cases (575 cases, 373 controls). Never-smokers with different genotypes and passive smoking status were compared with regard to occurrence of MS, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). The potential interaction between different genotypes and passive smoking was evaluated by calculating the attributable proportion (AP) due to interaction. An interaction was observed between passive smoking and carriage of HLA-DRB1*15 (AP 0.3, 95% CI 0.02-0.5 in the incident study, and AP 0.4, 95% CI 0.1-0.7 in the prevalent study), as well as between passive smoking and absence of HLA-A*02. Compared with non-smokers without any of these two genetic risk factors, non-exposed subjects with the two risk genotypes displayed an OR of 4.5 (95% CI 3.3-6.1) whereas the same genotype for subjects exposed to passive smoking rendered an OR of 7.7 (95% CI 5.5-10.8). The risk of developing MS associated with different HLA genotypes may be influenced by exposure to passive smoking. The finding supports our hypothesis that priming of the immune response in the lungs may subsequently lead to MS in people with a genetic susceptibility to the disease.

Authors: Hedström AK; Bomfim IL; Barcellos LF; Briggs F; Schaefer C; Kockum I; Olsson T; Alfredsson L

Int J Epidemiol. 2014 Dec;43(6):1791-8. Epub 2014-10-15.

PubMed abstract

Seroprevalence of Aquaporin-4-IgG in a Northern California Population Representative Cohort of Multiple Sclerosis

Using an aquaporin-4 (AQP4) M1-isoform-specific enzyme-linked immunosorbent assay (ELISA) and a fixed transfected cell-based assay (CBA), we tested AQP4-IgG in a northern California population representative cohort of 3293 potential cases with multiple sclerosis (MS). Seropositive cases were tested additionally by fluorescence-activated cell sorting, a live transfected cell-based assay. Sera samples were available in 1040 cases; 7 yielded positive results, 4 by ELISA alone and 3 by both ELISA and CBA. Clinical data (episodes of optic neuritis and longitudinally extensive transverse myelitis [reported on at least 1 magnetic resonance imaging spine]) supported the alternative diagnosis of neuromyelitis optica for 2 patients as seropositive by both ELISA and CBA. These 2 patients alone tested positive by a fluorescence-activated cell-sorting assay. The diagnosis of MS was considered correct in the other 5 patients. Thus, 5 ELISA results and 1 fixed CBA result were false positive. Sensitive serological evaluation for AQP4-IgG in this large population-representative cohort of predominantly white non-Hispanic patients with MS reveals that neuromyelitis optica spectrum disorder is rarely misdiagnosed as MS in contemporary US neurological practice (0.2%). The frequency of a false-positive result for ELISA and CBA in this MS cohort were 0.5% and 0.1%, respectively. This finding reflects the superior specificity of CBA and justifies caution in interpreting AQP4-IgG results obtained by ELISA.

Authors: Pittock SJ; Lennon VA; Bakshi N; Shen L; McKeon A; Quach H; Briggs FB; Bernstein AL; Schaefer CA; Barcellos LF

JAMA Neurol. 2014 Nov;71(11):1433-6.

PubMed abstract

Estimating genotype error rates from high-coverage next-generation sequence data

Exome and whole-genome sequencing studies are becoming increasingly common, but little is known about the accuracy of the genotype calls made by the commonly used platforms. Here we use replicate high-coverage sequencing of blood and saliva DNA samples from four European-American individuals to estimate lower bounds on the error rates of Complete Genomics and Illumina HiSeq whole-genome and whole-exome sequencing. Error rates for nonreference genotype calls range from 0.1% to 0.6%, depending on the platform and the depth of coverage. Additionally, we found (1) no difference in the error profiles or rates between blood and saliva samples; (2) Complete Genomics sequences had substantially higher error rates than Illumina sequences had; (3) error rates were higher (up to 6%) for rare or unique variants; (4) error rates generally declined with genotype quality (GQ) score, but in a nonlinear fashion for the Illumina data, likely due to loss of specificity of GQ scores greater than 60; and (5) error rates increased with increasing depth of coverage for the Illumina data. These findings, especially (3)-(5), suggest that caution should be taken in interpreting the results of next-generation sequencing-based association studies, and even more so in clinical application of this technology in the absence of validation by other more robust sequencing or genotyping methods.

Authors: Wall JD; Tang LF; Zerbe B; Kvale MN; Kwok PY; Schaefer C; Risch N

Genome Res. 2014 Nov;24(11):1734-9. Epub 2014-10-10.

PubMed abstract

Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors

To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors. Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied. In analyses stratified by gender, being overweight at ages 10 and 20 were associated with MS in females (p<0.01). Estimates trended in the same direction for males, but were not significant. BMI in 20s demonstrated a linear relationship with MS (p-trend=9.60×10(-4)), and a twofold risk of MS for females with a BMI?30kg/m(2) was observed (OR=2.15, 95% CI 1.18, 3.92). Significant associations between BMI in 20s and MS in males were not observed. Multivariate modelling demonstrated that significant associations between BMI or body size with MS in females persisted after adjusting for history of infectious mononucleosis and genetic risk factors, including HLA-DRB1*15:01 and established non-HLA risk alleles. Results show that childhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors.

Authors: Gianfrancesco MA; Schaefer C; Barcellos LF; et al.

Obes Res Clin Pract. 2014 Sep-Oct;8(5):e435-47. Epub 2014-03-06.

PubMed abstract

Smoking and Risk of Multiple Sclerosis: Evidence of Modification by NAT1 Variants

Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers. A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden. Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17-1.93]; in Sweden, OR = 1.35 [1.04-1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (P(corrected) < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19-2.56]; Sweden, OR = 1.62 [1.05-2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17-12.33]). We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.

Authors: Briggs FB; Schaefer C; Barcellos LF; et al.

Epidemiology. 2014 Jul;25(4):605-14.

PubMed abstract

Adverse socioeconomic position during the life course is associated with multiple sclerosis

Adverse socioeconomic position (SEP) in childhood and adulthood is associated with a proinflammatory phenotype, and therefore an important exposure to consider for multiple sclerosis (MS), a complex neuroinflammatory autoimmune disease. The objective was to determine whether SEP over the life course confers increased susceptibility to MS. 1643 white, non-Hispanic MS case and control members recruited from the Kaiser Permanente Medical Care Plan, Northern California Region, for which comprehensive genetic, clinical and environmental exposure data have been collected were studied. Logistic regression models investigated measures of childhood and adulthood SEP, and accounted for effects due to established MS risk factors, including HLA-DRB1*15:01 allele carrier status, smoking history, history of infectious mononucleosis, family history of MS and body size. Multiple measures of childhood and adulthood SEP were significantly associated with risk of MS, including parents renting versus owning a home at age 10: OR=1.48, 95% CI 1.09 to 2.02, p=0.013; less than a college education versus at least a college education based on parental household: OR=1.28, 95% CI 1.01 to 1.63, p=0.041; low versus high life course SEP: OR=1.50, 95% CI 1.09 to 2.05, p=0.012; and low versus high social mobility: OR=1.74, 95% CI 1.27 to 2.39, p=5.7×10(-4). Results derived from a population-representative case-control study provide support for the role of adverse SEP in MS susceptibility and add to the growing evidence linking lower SEP to poorer health outcomes. Both genetic and environmental contributions to chronic conditions are important and must be characterised to fully understand MS aetiology.

Authors: Briggs FB; Acuña BS; Shen L; Bellesis KH; Ramsay PP; Quach H; Bernstein A; Schaefer C; Barcellos LF

J Epidemiol Community Health. 2014 Jul;68(7):622-9. Epub 2014-02-27.

PubMed abstract

Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring

The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features. The study used a nested case-control design in the Child Health and Development Study birth cohort. In all, 85 individuals with bipolar disorder were identified following extensive ascertainment and diagnostic assessment and matched to 170 comparison subjects in the analysis. Serological documentation of maternal exposure to influenza was determined using the hemagglutination inhibition assay. No association was observed between serologically documented maternal exposure to influenza and bipolar disorder in offspring. However, maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features. The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.

Authors: Canetta SE; Bao Y; Co MD; Ennis FA; Cruz J; Terajima M; Shen L; Kellendonk C; Schaefer CA; Brown AS

Am J Psychiatry. 2014 May 1;171(5):557-63.

PubMed abstract

Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis

We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS). We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression. Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction. In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status. Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status. In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5-35.2) compared to nonobese subjects without the genetic risk factors. The corresponding OR in the prevalent study was 13.8 (95% CI 4.1-46.8). We observed striking interactions between BMI status and HLA genotype with regard to MS risk. Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule-restricted arm of the immune system, causing MS. Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease.

Authors: Hedström AK; Lima Bomfim I; Barcellos L; Gianfrancesco M; Schaefer C; Kockum I; Olsson T; Alfredsson L

Neurology. 2014 Mar 11;82(10):865-72. Epub 2014-02-05.

PubMed abstract

Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity

​BACKGROUND:Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count.METHODS:Hispanic CCM1 patients (n=188) harboring the founder Q455X ‘common Hispanic mutation’ (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways.RESULTS:At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean ± standard deviation (SD) of 60.1±115.0 (range 0-713) for total lesions and 4.9±8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE=0.31), 0.81 (SE=0.17), and 0.48 (SE=0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p≤0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p=0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count.CONCLUSIONS:These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sample sizes are needed to confirm these findings.

Authors: Choquet H; Pawlikowska L; Nelson J; McCulloch CE; Akers A; Baca B; Khan Y; Hart B; Morrison L; Kim H; Brain Vascular Malformation Consortium (BVMC) Study

Cerebrovasc Dis. 2014;38(6):433-40. doi: 10.1159/000369200. Epub 2014 Dec 3.

PubMed abstract

Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation

​BACKGROUND:Cerebral cavernous malformations (CCM) are enlarged vascular lesions affecting 0.1-0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age. The number of lesions varies widely for unknown reasons, even among carriers of similar ages with the same mutation. The purpose of this study was to investigate whether cardiovascular (CV) risk factors influence potential markers of familial CCM1 disease severity, such as lesion count and history of intracerebral hemorrhage.METHODS:We analyzed baseline data from 185 Hispanic subjects, enrolled in the Brain Vascular Malformation Consortium study between June 2010 and March 2013. All subjects were carriers of the founder Q455X ‘Common Hispanic Mutation’ (CHM) in the KRIT1 gene, and had a clinical diagnosis of CCM or had an affected first- or second-degree relative with CCM. We performed a cross-sectional study, collecting detailed clinical information of CCM1-CHM subjects and cerebral susceptibility-weighted magnetic resonance imaging to assess lesion count. Linear or logistic regression analysis of log-lesion count or history of intracerebral hemorrhage and CV risk factors (age, gender, obesity, diabetes, hypertension, hyperlipidemia and smoking status) and related quantitative traits (body mass index, glycosylated hemoglobin levels, blood pressure, lipids levels and pack-years of cigarette smoking) was performed accommodating familial clustering.RESULTS:CCM1-CHM subjects were mainly female (63.8%) and symptomatic at presentation (63.2%). Lesion count was highly variable (mean ± SD: 57.7 ± 110.6; range: 0-713); 90% of CCM1-CHM subjects had multiple lesions at enrollment. Age (p < 0.001) was positively correlated with lesion count and male gender (p = 0.035) was associated with a greater number of lesions. Obesity (p = 0.001) and higher body mass index (p = 0.002) were associated with fewer lesions. No association with hypertension was detected, however, systolic blood pressure (p = 0.002) was associated with fewer lesions. No significant association with lesion count was observed for diabetes, hyperlipidemia, smoking status or for related quantitative traits. History of intracerebral hemorrhage was not significantly associated with any CV risk factors, however, we found borderline associations of hemorrhage with obesity (p = 0.062), systolic blood pressure (p = 0.083) and pack-years of cigarette smoking (p = 0.055). After correction for multiple testing, age and obesity remained significantly associated with lesion count in CCM1-CHM subjects.CONCLUSIONS:These results suggest that several CV risk factors explain some of the variability in lesion count in Hispanic CCM1-CHM subjects. Although age, gender, obesity, body mass index and systolic blood pressure may influence familial CCM1 disease severity, further longitudinal studies in larger sample sizes are essential to confirm these findings.

Authors: Choquet H; Nelson J; Pawlikowska L; McCulloch CE; Akers A; Baca B; Khan Y; Hart B; Morrison L; Kim H.

Cerebrovasc Dis. 2014;37(1):57-63. doi: 10.1159/000356839. Epub 2013 Dec 21.

PubMed abstract

The effect of bariatric surgery on psychiatric course among patients with bipolar disorder

Bariatric surgery is the most effective therapy for severe obesity. People with bipolar disorder have increased risk of obesity, yet are sometimes considered ineligible for bariatric surgery due to their bipolar disorder diagnosis. This study aimed to determine if bariatric surgery alters psychiatric course among stable patients with bipolar disorder. A matched cohort study (2006-2009) with mean follow-up of 2.17 years was conducted within Kaiser Permanente Northern California, a group practice integrated health services delivery organization that provides medical and psychiatric care to 3.3 million people. Participants were 144 severely obese patients with bipolar disorder who underwent bariatric surgery, and 1,440 control patients with bipolar disorder, matched for gender, medical center, and contemporaneous health plan membership. Controls met referral criteria for bariatric surgery. Hazard ratio for psychiatric hospitalization, and change in rate of outpatient psychiatric utilization from baseline to Years 1 and 2, were compared between groups. A total of 13 bariatric surgery patients (9.0%) and 153 unexposed to surgery (10.6%) had psychiatric hospitalization during follow-up. In multivariate Cox models adjusting for potential confounding factors, the hazard ratio of psychiatric hospitalization associated with bariatric surgery was 1.03 [95% confidence interval (CI): 0.83-1.23]. In fully saturated multivariate general linear models, change in outpatient psychiatric utilization was not significantly different for surgery patients versus controls, from baseline to Year 1 (-0.4 visits/year, 95% CI: -0.5 to 0.4) or baseline to Year 2 (0.4 visits/year, 95% CI: -0.1 to 1.0). Bariatric surgery did not affect psychiatric course among stable patients with bipolar disorder. The results of this study suggest that patients with bipolar disorder who have been evaluated as stable can be considered for bariatric surgery.

Authors: Ahmed AT; Warton EM; Schaefer CA; Shen L; McIntyre RS

Bipolar Disord. 2013 Nov;15(7):753-63. Epub 2013-08-05.

PubMed abstract

Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Authors: Patsopoulos NA; Barcellos LF; Schaefer C; de Bakker PI; et al.

PLoS Genet. 2013 Nov;9(11):e1003926. Epub 2013-11-21.

PubMed abstract

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Authors: International Multiple Sclerosis Genetics Consortium (IMSGC); Barcellos LF; Schaefer C; McCauley JL; et al.

Nat Genet. 2013 Nov;45(11):1353-60. Epub 2013-09-29.

PubMed abstract

Maternal smoking during pregnancy and bipolar disorder in offspring

OBJECTIVE: Maternal smoking during pregnancy is associated with a number of adverse externalizing outcomes for offspring from childhood to adulthood. The relationship between maternal smoking and bipolar disorder in offspring, which includes externalizing symptoms among its many manifestations, has not been investigated in depth. The authors examined whether offspring exposed to maternal smoking in utero would be at increased lifetime risk for bipolar disorder after accounting for other factors related to maternal smoking. METHOD: Individuals with bipolar disorder (N=79) were ascertained from the birth cohort of the Child Health and Development Study. Case subjects were identified by a combination of clinical, database, and direct mailing sources; all case subjects were directly interviewed and diagnosed using DSM-IV criteria. Comparison subjects (N=654) were matched to case subjects on date of birth (+/-30 days), sex, membership in the cohort at the time of illness onset, and availability of maternal archived sera. RESULTS: After adjusting for potential confounders, offspring exposed to in utero maternal smoking exhibited a twofold greater risk for bipolar disorder (odds ratio=2.014, 95% confidence interval=1.48-2.53, p=0.01). The associations were noted primarily among bipolar offspring without psychotic features. CONCLUSIONS: Prenatal tobacco exposure may be one suspected cause of bipolar disorder. However, it will be necessary to account for other unmeasured familial factors before causal teratogenic effects can be suggested.

Authors: Talati A; Bao Y; Kaufman J; Shen L; Schaefer CA; Brown AS

Am J Psychiatry. 2013 Oct 1;170(10):1178-85.

PubMed abstract

Parental age and risk of bipolar disorder in offspring

We investigated prospectively documented parental age and bipolar disorder (BD) in a multi-ethnic birth cohort. The study was based on a nested case-control design from the Child Health and Development Study (CHDS) birth cohort from 1959 to 1966. Potential cases with BD were ascertained by database linkages between CHDS, Kaiser Permanente Medical Care Plan (KPNC), and Alameda County Behavioral Health Care Services, and mailed questionnaires. Consensus diagnoses with the SCID for DSM-IV-TR were made. The total number of BD cases was 94. Controls (N=746) were selected from the birth cohort and matched on date of birth, sex, and KPNC membership or residence in Alameda County. For every 10-year increment of paternal age, there was no significant association with BD, adjusting for maternal age. There was also no significant association between maternal age, modeled in 10-year increments, and risk of BD after adjustment for paternal age and maternal race, although there was a suggestion for a protective relationship between increasing maternal age and BD with psychotic features. These findings suggest that if advanced paternal age is a risk factor for BD, the strength of the relationship is small.

Authors: Brown A; Bao Y; McKeague I; Shen L; Schaefer C

Psychiatry Res. 2013 Aug 15;208(3):225-31. Epub 2013-06-19.

PubMed abstract

Examination of rare missense variants in the CHRNA5-A3-B4 gene cluster to level of response to alcohol in the San Diego Sibling Pair study

​BACKGROUND:Common variants in the CHRNA5-A3-B4 gene cluster have been shown to be associated with nicotine dependence and alcohol use disorders (AUDs) and related traits, including the level of response (LR) to alcohol. Recently, rare variants (MAF < 0.05) in CHRNB4 have been reported to be associated with a decreased risk of developing nicotine dependence. However, the role of rare variants in the CHRNA5-A3-B4 gene cluster to the LR to alcohol has not yet been established.METHODS:To determine whether rare variants in the CHRNA5-A3-B4 gene cluster contribute to the LR to alcohol, the coding regions of these 3 genes were sequenced in 538 subjects from the San Diego Sibling Pair study.RESULTS:The analyses identified 16 rare missense variants, 9 of which were predicted to be damaging using in silico analysis tools. Carriers of these variants were compared to noncarriers using a family-based design for each gene and for the gene cluster as a whole. In these analyses, a CHRNA5 carrier status was significantly associated with the phenotype related to the feeling of intoxication experienced during the alcohol challenge (p = 0.039).CONCLUSIONS:These results indicate that rare genetic variation in the CHRNA5-A3-B4 gene cluster contributes modestly to the LR to alcohol in the San Diego Sibling Pair study and may protect against AUDs. However, replication studies are needed to confirm our findings.

Authors: Choquet H; Joslyn G; Lee A; Kasberger J; Robertson M; Brush G; Schuckit MA; White R; Jorgenson E

Alcohol Clin Exp Res. 2013 Aug;37(8):1311-6. doi: 10.1111/acer.12099. Epub 2013 Mar 4.

PubMed abstract

Gestational Influenza and Bipolar Disorder in Adult Offspring

IMPORTANCE: Gestational influenza has been associated previously with schizophrenia in offspring, but the relationship between this exposure and bipolar disorder (BD) is unclear. The identification of gestational influenza as a risk factor for BD may have potential for preventive approaches. OBJECTIVE: To test the hypothesis that maternal influenza during pregnancy is related to BD among offspring. DESIGN: Nested case-control study of a population-based birth cohort from the Child Health and Development Study (CHDS). From January 1, 1959, through December 31, 1966, the CHDS recruited nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). Data on treated maternal influenza from the CHDS were used. Potential cases with BD from the cohort were identified by database linkages of identifiers among the CHDS, Kaiser Permanente database, and a large county health care database; by a mailed questionnaire to the CHDS cohort with subsequent interviews; and from an earlier psychiatric follow-up study on this birth cohort. SETTING: The CHDS, Kaiser Permanente, and county health care databases. PARTICIPANTS: Cases of BD (n = 92) confirmed by structured research interviews and consensus diagnosis among the 214 subjects (48% of those ascertained) who participated and control subjects (n = 722) matched on date of birth, sex, and membership in KPNC or residence in Alameda County. EXPOSURES: Influenza. MAIN OUTCOME AND MEASURES: Bipolar I or II disorder, BD not otherwise specified, or BD with psychotic features. RESULTS: We found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; P = .003]) after exposure to maternal influenza at any time during pregnancy. The findings were not confounded by maternal age, race, educational level, gestational age at birth, and maternal psychiatric disorders. CONCLUSIONS AND RELEVANCE: Maternal influenza may be a risk factor for BD. Although replication is required, the findings suggest that prevention of maternal influenza during pregnancy may reduce the risk of BD.

Authors: Parboosing R; Bao Y; Shen L; Schaefer CA; Brown AS

JAMA Psychiatry. 2013 Jul;70(7):677-85.

PubMed abstract

​Genetic analysis of a population heavy drinking phenotype identifies risk variants in whites

​Genetic association studies thus far have used detailed diagnoses of alcoholism to identify loci associated with risk. This proof-of-concept analysis examined whether population data of lifetime heaviest alcohol consumption may be used to identify genetic loci that modulate risk. We conducted a genetic association study in European Americans between variants in approximately 2100 genes and alcohol consumption as part of the Candidate gene Association Resource project. We defined cases as individuals with a history of drinking 5 or more drinks per day almost every day of the week and controls as current light drinkers (1-5 drinks per week). We cross-validated identified single nucleotide polymorphisms in a meta-analysis of 2 cohorts of unrelated individuals–Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)–and in a separate cohort of related individuals–Framingham Heart Study (FHS). The most significant variant in the meta-analysis of ARIC and CHS was rs6933598 in methylenetetrahydrofolate dehydrogenase (P = 7.46 × 10(-05)) with a P value in FHS of 0.042. The top variants in FHS were rs12249562 in cubulin (P = 3.03 × 10(-05)) and rs9839267 near cholecystokinin (P = 3.05 × 10(-05)) with a P value of 0.019 for rs9839267 in CHS. We have here shown feasibility in evaluating lifetime incidence of heavy alcohol drinking from population-based studies for the purpose of conducting genetic association analyses.

Authors: Hamidovic A; Goodloe RJ; Young TR; Styn MA; Mukamal KJ; Choquet H; Kasberger JL; Buxbaum SG; Papanicolaou GJ; White W; Volcik K; Spring B; Hitsman B; Levy D; Jorgenson E.;

​J Clin Psychopharmacol. 2013 Apr;33(2):206-10. doi: 10.1097/JCP.0b013e318287009a.

PubMed abstract

Contribution of common PCSK1 genetic variants to obesity in 8,359 subjects from multi-ethnic American population

​Common PCSK1 variants (notably rs6232 and rs6235) have been shown to be associated with obesity in European, Asian and Mexican populations. To determine whether common PCSK1 variants contribute to obesity in American population, we conducted association analyses in 8,359 subjects using two multi-ethnic American studies: the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Multi-Ethnic Study of Atherosclerosis (MESA). By evaluating the contribution of rs6232 and rs6235 in each ethnic group, we found that in European-American subjects from CARDIA, only rs6232 was associated with BMI (P = 0.006) and obesity (P = 0.018) but also increased the obesity incidence during the 20 years of follow-up (HR = 1.53 [1.07-2.19], P = 0.019). Alternatively, in African-American subjects from CARDIA, rs6235 was associated with BMI (P = 0.028) and obesity (P = 0.018). Further, by combining the two case-control ethnic groups from the CARDIA study in a meta-analysis, association between rs6235 and obesity risk remained significant (OR = 1.23 [1.05-1.45], P = 9.5×10(-3)). However, neither rs6232 nor rs6235 was associated with BMI or obesity in the MESA study. Interestingly, rs6232 was associated with BMI (P = 4.2×10(-3)) and obesity (P = 3.4×10(-3)) in the younger European-American group combining samples from the both studies [less than median age (53 years)], but not among the older age group (P = 0.756 and P = 0.935 for BMI and obesity, respectively). By combining all the case-control ethnic groups from CARDIA and MESA in a meta-analysis, we found no significant association for the both variants and obesity risk. Finally, by exploring the full PCSK1 locus, we observed that no variant remained significant after correction for multiple testing. These results indicate that common PCSK1 variants (notably rs6232 and rs6235) contribute modestly to obesity in multi-ethnic American population. Further, these results suggest that the association of rs6232 with obesity may be age-dependent in European-Americans. However, multiple replication studies in multi-ethnic American population are needed to confirm our findings.

Authors: Choquet H; Kasberger J; Hamidovic A; Jorgenson E

PLoS One. 2013;8(2):e57857. doi: 10.1371/journal.pone.0057857. Epub 2013 Feb 25.

PubMed abstract

Impact of type 2 diabetes on lower urinary tract symptoms in men: a cohort study

BACKGROUND: Studies of the impact of type 2 diabetes on the prevalence and incidence of lower urinary tract symptoms (LUTS) among men have provided divergent results. We sought to examine this issue using two large and diverse cohorts. METHODS: This study used questionnaire and clinical data from two large multiethnic cohorts, the California Men’s Health Study (CMHS) and Research Program in Genes, Environment and Health (RPGEH). Diabetes characteristics data were derived from questionnaire and Diabetes Registry data. LUTS were measured using a standardized scale. Socioeconomic and comorbidity data were obtained by self-report. Multivariable logistic regression analysis was used to examine the association between baseline DM status and prevalence and incidence of LUTS, with adjustment for potential confounding variables. RESULTS: We found type 2 diabetes to be associated with prevalent LUTS (odds ratio (OR) = 1.32, 95% confidence interval (CI) 1.26, 1.38). The association was stronger among men with type 2 diabetes who were on active pharmaceutical treatment and had it for a longer duration. No association was observed between type 2 diabetes and new onset LUTS. CONCLUSIONS: Type 2 diabetes increases the risk of LUTS.

Authors: Van Den Eeden SK; Ferrara A; Shan J; Jacobsen SJ; Quinn VP; Haque R; Quesenberry CP

BMC Urol. 2013 Feb 20;13:12.

PubMed abstract

Low maternal retinol as a risk factor for schizophrenia in adult offspring

BACKGROUND: Prenatal micronutrient deficiency has been linked to later development of schizophrenia among offspring; however, no study has specifically investigated the association between vitamin A and this disorder. Vitamin A is an essential nutrient which is required by the early embryo and fetus for gene expression and regulation, cell differentiation, proliferation and migration. Previous work suggests that vitamin A deficiency in the second trimester may be particularly relevant to the etiopathogenesis of neurobehavioral phenotypes some of which are observed in schizophrenia. METHODS: We examined whether low maternal vitamin A levels in the second trimester are associated with the risk of schizophrenia and other schizophrenia spectrum disorders (SSD) in the Prenatal Determinants of Schizophrenia study; third trimester vitamin A levels were also examined in relation to SSD. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Archived maternal serum samples were assayed for vitamin A in cases (N=55) and up to 2 controls per case (N=106) matched on length of membership in the health plan, date of birth (+/-28days), sex, and gestational timing and availability of archived maternal sera. RESULTS: For the second trimester, low maternal vitamin A, defined as values in the lowest tertile of the distribution among controls, was associated with a greater than threefold increased risk of SSD, adjusting for maternal education and age (OR=3.04, 95% CI=1.06, 8.79, p=.039). No association between third trimester maternal vitamin A and SSD was observed. CONCLUSIONS: Although further investigations are warranted, this is the first birth cohort study to our knowledge to report an association between low maternal vitamin A levels and SSD among offspring.

Authors: Bao Y; Ibram G; Blaner WS; Quesenberry CP; Shen L; McKeague IW; Schaefer CA; Susser ES; Brown AS

Schizophr Res. 2012 May;137(1-3):159-65. Epub 2012 Feb 29.

PubMed abstract

Midlife vs Late-Life Depressive Symptoms and Risk of Dementia: Differential Effects for Alzheimer Disease and Vascular Dementia

CONTEXT: Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia. OBJECTIVE: To clarify the timing and nature of the association between depression and dementia. DESIGN: We examined depressive symptoms assessed in midlife (1964-1973) and late life (1994-2000) and the risks of dementia, Alzheimer disease (AD), and vascular dementia (VaD) (2003-2009) in a retrospective cohort study. Depressive symptoms were categorized as none, midlife only, late life only, or both. Cox proportional hazards models (age as timescale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD, or VaD. SETTING: Kaiser Permanente Medical Care Program of Northern California. PARTICIPANTS: Thirteen thousand five hundred thirty-five long-term Kaiser Permanente members. Main Outcome Measure Any medical record diagnosis of dementia or neurology clinic diagnosis of AD or VaD. RESULTS: Subjects had a mean (SD) age of 81.1 (4.5) years in 2003, 57.9% were women, and 24.2% were nonwhite. Depressive symptoms were present in 14.1% of subjects in midlife only, 9.2% in late life only, and 4.2% in both. During 6 years of follow-up, 22.5% were diagnosed with dementia (5.5% with AD and 2.3% with VaD). The adjusted hazard of dementia was increased by approximately 20% for midlife depressive symptoms only (hazard ratio, 1.19 [95% CI, 1.07-1.32]), 70% for late-life symptoms only (1.72 [1.54-1.92]), and 80% for both (1.77 [1.52-2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a 2-fold increase in AD risk (hazard ratio, 2.06 [95% CI, 1.67-2.55]), whereas subjects with midlife and late-life symptoms had more than a 3-fold increase in VaD risk (3.51 [2.44-5.05]). CONCLUSIONS: Depressive symptoms in midlife or in late life are associated with an increased risk of developing dementia. Depression that begins in late life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.

Authors: Barnes DE; Yaffe K; Byers AL; McCormick M; Schaefer C; Whitmer RA

Arch Gen Psychiatry. 2012 May;69(5):493-8.

PubMed abstract

New Models for Large Prospective Studies: Is There a Better Way?

Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the ‘UK Biobank,’ which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which ‘process’ expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin.

Authors: Manolio TA; Schaefer C; Collins FS; et al.

Am J Epidemiol. 2012 May 1;175(9):859-66. Epub 2012 Mar 12.

PubMed abstract

Gene-centric analysis of serum cotinine levels in African and European American populations

​To date, most genetic association studies of tobacco use have been conducted in European American subjects using the phenotype of smoking quantity (cigarettes per day). However, smoking quantity is a very imprecise measure of exposure to tobacco smoke constituents. Analyses of alternate phenotypes and populations may improve our understanding of tobacco addiction genetics. Cotinine is the major metabolite of nicotine, and measuring serum cotinine levels in smokers provides a more objective measure of nicotine dose than smoking quantity. Previous genetic association studies of serum cotinine have focused on individual genes. We conducted a genetic association study of the biomarker in African American (N=365) and European American (N=315) subjects from the Coronary Artery Risk Development in Young Adults study using a chip containing densely-spaced tag SNPs in ∼2100 genes. We found that rs11187065, located in the non-coding region (intron 1) of insulin-degrading enzyme (IDE), was the most strongly associated SNP (p=8.91 × 10(-6)) in the African American cohort, whereas rs11763963, located on chromosome 7 outside of a gene transcript, was the most strongly associated SNP in European Americans (p=1.53 × 10(-6)). We then evaluated how the top variant association in each population performed in the other group. We found that the association of rs11187065 in IDE was also associated with the phenotype in European Americans (p=0.044). Our top SNP association in European Americans, rs11763963 was non-polymorphic in our African American sample. It has been previously shown that psychostimulant self-administration is reduced in animals with lower insulin because of interference with dopamine transmission in the brain reward centers. Our finding provides a platform for further investigation of this, or additional mechanisms, involving the relationship between insulin and self-administered nicotine dose.

Authors: Hamidovic A; Goodloe RJ; Bergen AW; Benowitz NL; Styn MA; Kasberger JL; Choquet H; Young TR; Meng Y; Palmer C; Pletcher M; Kertesz S; Hitsman B; Spring B; Jorgenson E

Neuropsychopharmacology. 2012 Mar;37(4):968-74. doi: 10.1038/npp.2011.280. Epub 2011 Nov 16.

PubMed abstract

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Authors: Ichimura A; Hirasawa A; Poulain-Godefroy O; Bonnefond A; Hara T; Yengo L; Kimura I; Leloire A; Liu N; Iida K; Choquet H; Besnard P; Lecoeur C; Vivequin S; Ayukawa K; Takeuchi M; Ozawa K; Tauber M; Maffeis C; Morandi A; Buzzetti R; Elliott P; Pouta A; Jarvelin MR; Körner A; Kiess W; Pigeyre M; Caiazzo R; Van Hul W; Van Gaal L; Horber F; Balkau B; Lévy-Marchal C; Rouskas K; Kouvatsi A; Hebebrand J; Hinney A; Scherag A; Pattou F; Meyre D; Koshimizu TA; Wolowczuk I; Tsujimoto G; Froguel P

Nature. 2012 Feb 19;483(7389):350-4. doi: 10.1038/nature10798.

PubMed abstract

Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity

​Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.

Authors: Creemers JW; Choquet H; Stijnen P; Vatin V; Pigeyre M; Beckers S; Meulemans S; Than ME; Yengo L; Tauber M; Balkau B; Elliott P; Jarvelin MR; Van Hul W; Van Gaal L; Horber F; Pattou F; Froguel P; Meyre D

Diabetes. 2012 Feb;61(2):383-90. doi: 10.2337/db11-0305. Epub 2011 Dec 30.

PubMed abstract

Evaluating Racial/Ethnic Disparities in Lower Urinary Tract Symptoms in Men

PURPOSE: We examined whether there are racial/ethnic disparities in lower urinary tract symptoms in men. MATERIALS AND METHODS: Racial/ethnic disparities were examined using the American Urological Association symptom index in 2 large cohorts, including the California Men’s Health Study and the Research Program in Genes, Environment and Health. Prevalence and incidence were calculated in each age and race/ethnicity strata. Multivariate analysis was done to assess the association between race/ethnicity and lower urinary tract symptoms. RESULTS: The lower urinary tract symptom prevalence increased with age in each racial/ethnic category (p <0.05). The mean +/- SD age adjusted American Urological Association symptom index score for black, Hispanic, other/mixed, nonHispanic white and Asian men was 9.57 +/- 5.83, 9.35 +/- 6.30, 9.32 +/- 6.22, 8.99 +/- 5.89 and 8.41 +/- 5.59, respectively. In multivariate models Hispanic and black men were at increased risk for moderate lower urinary tract symptoms than white men while only Hispanic men were at higher risk for severe lower urinary tract symptoms. Asian men were at lower risk for moderate or severe lower urinary tract symptoms than white men. The incident rate of lower urinary tract symptoms increased with increasing baseline age for almost all racial/ethnic groups (range 32% to 56%). Asian and Hispanic men were at lower risk for incident lower urinary tract symptoms than white men even after adjusting for sociodemographic factors, health related behaviors and comorbidity. CONCLUSIONS: Racial/ethnic disparities in lower urinary tract symptoms persist after accounting for putative and established risk factors.

Authors: Van Den Eeden SK; Shan J; Jacobsen SJ; Aaronsen D; Haque R; Quinn VP; Quesenberry CP Jr; Urologic Diseases in America Project

J Urol. 2012 Jan;187(1):185-9. Epub 2011 Nov 17.

PubMed abstract

Design and coverage of high throughput genotyping arrays optimized for individuals of East Asian, African American, and Latino race/ethnicity using imputation and a novel hybrid SNP selection algorithm

Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array (712,930 SNPs) was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.

Authors: Hoffmann TJ; Iribarren C; Quesenberry C; Van den Eeden SK; Whitmer RA; Schaefer C; Risch N; et al.

Genomics. 2011 Dec;98(6):422-30. Epub 2011 Aug 28.

PubMed abstract

​Is rigorous retrospective harmonization possible? Application of the DataSHaPER approach across 53 large studies.

​BACKGROUND: Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies.METHODS: This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored.RESULTS: Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized.CONCLUSION: The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases.

Authors: Fortier I; Doiron D; Little J; Ferretti V; L'Heureux F; Stolk RP; Knoppers BM; Hudson TJ; Burton PR; International Harmonization Initiative;

​Int J Epidemiol. 2011 Oct;40(5):1314-28. doi: 10.1093/ije/dyr106. Epub 2011 Jul 30.

PubMed abstract

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Authors: International Multiple Sclerosis Genetics Consortium; Barcellos LF; Schaefer CA; Compston A; et al.

Nature. 2011 Aug 10;476(7359):214-9.

PubMed abstract

Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array

The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.

Authors: Hoffmann TJ; Iribarren C; Quesenberry C; Van den Eeden SK; Whitmer RA; Schaefer C; Risch N; et al.

Genomics. 2011 Aug;98(2):79-89. Epub 2011 Apr 30.

PubMed abstract

Maternal serum docosahexaenoic acid and schizophrenia spectrum disorders in adult offspring

It is believed that during mid-to-late gestation, docosahexaenoic acid (DHA), an n-3 fatty acid, plays an important role in fetal and infant brain development, including neurocognitive and neuromotor functions. Deficits in several such functions have been associated with schizophrenia. Though sufficient levels of DHA appear to be important in neurodevelopment, elevated maternal DHA levels have also been associated with abnormal reproductive outcomes in both animal models and humans. Our objective was to assess whether a disturbance in maternal DHA levels, measured prospectively during pregnancy, was associated with risk of schizophrenia and other schizophrenia spectrum disorders (SSD) in adult offspring. In order to test the hypothesis that abnormal levels of DHA are associated with SSD, a case-control study nested within a large, population-based birth cohort, born from 1959 through 1967 and followed up for SSD from 1981 through 1997, was utilized. Maternal levels of both DHA and arachidonic acid (AA), an n-6 fatty acid, were analyzed in archived maternal sera from 57 cases of SSD and 95 matched controls. There was a greater than twofold increased risk of SSD among subjects exposed to maternal serum DHA in the highest tertile (OR=2.38, 95% CI=1.19, 4.76, p=0.01); no such relationship was found between AA and SSD. These findings suggest that elevated maternal DHA is associated with increased risk for the development of SSD in offspring.

Authors: Harper KN; Hibbeln JR; Deckelbaum R; Quesenberry CP Jr; Schaefer CA; Brown AS

Schizophr Res. 2011 May;128(1-3):30-6. Epub 2011 Feb 15.

PubMed abstract

Executive Function in Preschool Children: Test-Retest Reliability

Research suggests that executive function (EF) may distinguish between children who are well- or ill-prepared for kindergarten, however, little is known about the test-retest reliability of measures of EF for children. We aimed to establish a battery of EF measures that are sensitive to both development and individual differences across the preschool period using Conflict and Delay subtests that had a cool (abstract) or hot (extrinsic reward) focus. Results from 151 children in three age groups (2.5, 3.5, and 4.5) suggested acceptable same-day test-retest reliability on all but Delay-Cool subtasks. These findings will inform appropriate measurement selection and development for future studies.

Authors: Beck DM; Schaefer C; Pang K; Carlson SM

J Cogn Dev. 2011 Jan 01;12(2):169-193.

PubMed abstract

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8

BACKGROUND: Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. METHODS: Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. RESULTS: Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. CONCLUSION: Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

Authors: Ellman LM; Deicken RF; Vinogradov S; Kremen WS; Poole JH; Kern DM; Tsai WY; Schaefer CA; Brown AS

Schizophr Res. 2010 Aug;121(1-3):46-54. Epub 2010 Jun 9.

PubMed abstract

Is pregnancy after breast cancer safe?

The impact of treatment on subsequent fertility and the safety of childbearing are major complicating factors for young women diagnosed with breast cancer. As national data indicate women are postponing first pregnancy to older ages; therefore, many young patients are seeking clinical guidance regarding the safety of conception and treatment options that may not prevent subsequent pregnancy. Newly developed chemotherapy protocols of brief duration have improved life expectancy enabling some women to consider childbearing. This study was conducted to compare prognosis among breast cancer patients with and without a subsequent pregnancy. Medical record review of female members of a Northern California prepaid health care plan enabled the identification of 107 women with one or more subsequent pregnancies and 344 cases without a pregnancy, who were diagnosed between 1968 and 1995. Sets were matched on age, year and stage at diagnosis, months of survival and recurrence status at conception. Among the matched sets, neither risk of recurrence nor death differed significantly by subsequent pregnancy history during an average 12 years of follow-up (adjusted hazard ratio [HR] recurrence: 1.2 [0.8, 2.0]; adjusted HR death: 1.0 [0.6, 1.9]). Women interested in preserving their fertility and considering pregnancy are a self-selected population; therefore, to reduce potential bias, cases were matched on recurrence status at time of conception. Although the number of cases was limited, subgroup analyzes indicated a small, nonsignificant adverse effect among women who conceived within 12 months of diagnosis. This analysis of carefully matched cases provides reassurance that long-term prognosis was not adversely affected by subsequent pregnancy.

Authors: Kranick JA; Schaefer C; Rowell S; Desai M; Petrek JA; Hiatt RA; Senie RT

Breast J. 2010 Jul-Aug;16(4):404-11. Epub 2010 May 26.

PubMed abstract

Cognitive decline in schizophrenia from childhood to midlife: a 33-year longitudinal birth cohort study

BACKGROUND: We examined cognitive deficits before and after onset of schizophrenia in a longitudinal study that: 1) covers a long time interval; 2) minimizes test unreliability by including the identical measure at both childhood and post-onset cognitive assessments; and 3) minimizes bias by utilizing a population-based sample in which participants were selected neither for signs of illness in childhood nor for being at risk for schizophrenia. METHODS: Participants in the present study, Developmental Insult and Brain Anomaly in Schizophrenia (DIBS), were ascertained from an earlier epidemiologic study conducted in Oakland, CA. The original version of the Peabody Picture Vocabulary Test (PPVT), a test of receptive vocabulary, was administered at age 5 or 9 and repeated as part of the DIBS study at an average age of 40. There were 10 DIBS cases with DSM-IV schizophrenia or schizoaffective disorder and 15 demographically similar DIBS controls with both child and adult PPVT scores. RESULTS: Cases scored significantly lower than controls in childhood (d=0.95) and adulthood (d=1.67). Residualized scores indicating the number of SDs above or below one’s predicted adult score revealed a mean case-control difference of -1.51SDs, consistent with significant relative decline over time among the cases (p<0.0013). CONCLUSIONS: In this prospective study, individuals who developed adult schizophrenia manifested impaired receptive vocabulary during childhood and further relative deterioration (or lack of expected improvement) between childhood and midlife. Limitations should also be acknowledged, including the small sample size and the fact that we cannot be certain when the continued deterioration took place.

Authors: Kremen WS; Vinogradov S; Poole JH; Schaefer CA; Deicken RF; Factor-Litvak P; Brown AS

Schizophr Res. 2010 May;118(1-3):1-5. Epub 2010 Feb 12.

PubMed abstract

Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia

OBJECTIVE: Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with schizophrenia. METHOD: The authors assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort. RESULTS: Patients who were exposed to infection in utero committed significantly more total errors on the Wisconsin Card Sorting Test and took significantly more time to complete the Trails B than unexposed patients. Exposed patients also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span. CONCLUSIONS: Prenatal infections previously associated with schizophrenia are related to impaired performance on the Wisconsin Card Sorting Test and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is needed to elucidate the specificity of prenatal infection to these executive function measures and to examine correlates with neuroanatomic and neurophysiologic anomalies.

Authors: Brown AS; Vinogradov S; Kremen WS; Poole JH; Deicken RF; Penner JD; McKeague IW; Kochetkova A; Kern D; Schaefer CA

Am J Psychiatry. 2009 Jun;166(6):683-90. Epub 2009 Apr 15.

PubMed abstract

Prenatal infection and cavum septum pellucidum in adult schizophrenia

Increased length of the cavum septum pellucidum (CSP) and in utero infection are each associated with increased risk of schizophrenia. Hence, we examined whether prenatal infections are related to CSP length in schizophrenia patients. In a well-characterized birth cohort, in utero infection was assessed using serologic biomarkers or physician diagnoses. Magnetic resonance images were acquired, and CSP length was quantified by a standard protocol. In utero infection was associated with increased CSP length in exposed schizophrenia cases compared to unexposed cases, suggesting that prenatal infection plays a role in a neurodevelopmental morphologic anomaly that has been related previously to schizophrenia.

Authors: Brown AS; Deicken RF; Vinogradov S; Kremen WS; Poole JH; Penner JD; Kochetkova A; Kern D; Schaefer CA

Schizophr Res. 2009 Mar;108(1-3):285-7. Epub 2009 Jan 8.

PubMed abstract

Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies

BACKGROUND: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. PURPOSE: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. DATA SOURCES: Studies identified in PubMed, Web of Science, and CancerLit. STUDY SELECTION: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. DATA EXTRACTION: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. DATA SYNTHESIS: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. LIMITATIONS: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. CONCLUSION: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

Authors: Roddam AW; Schaefer C; Quesenberry CP Jr; Galan P; et al.

Ann Intern Med. 2008 Oct 7;149(7):461-71, W83-8.

PubMed abstract

Maternal iron deficiency and the risk of schizophrenia in offspring

CONTEXT: Iron is essential for brain development and functioning. Emerging evidence suggests that iron deficiency in early life leads to long-lasting neural and behavioral deficits in infants and children. Adopting a life course perspective, we examined the effects of early iron deficiency on the risk of schizophrenia in adulthood. OBJECTIVE: To determine whether maternal iron deficiency, assessed by maternal hemoglobin concentration during pregnancy, increases the susceptibility to schizophrenia spectrum disorders (SSDs) among offspring. DESIGN: Data were drawn from a population-based cohort born from 1959 through 1967 and followed up for development of SSD from 1981 through 1997. PARTICIPANTS: Of 6872 offspring for whom maternal hemoglobin concentration was available, 57 had SSDs (0.8%) and 6815 did not (99.2%). MAIN OUTCOME MEASURE: Prospectively assayed, the mean value of maternal hemoglobin concentration was the primary exposure. Hemoglobin concentration was analyzed as a continuous and a categorical variable. RESULTS: A mean maternal hemoglobin concentration of 10.0 g/dL or less was associated with a nearly 4-fold statistically significant increased rate of SSDs (adjusted rate ratio, 3.73; 95% confidence interval, 1.41-9.81; P = .008) compared with a mean maternal hemoglobin concentration of 12.0 g/dL or higher, adjusting for maternal education and ethnicity. For every 1-g/dL increase in mean maternal hemoglobin concentration, a 27% decrease in the rate of SSDs was observed (95% confidence interval, 0.55-0.96; P = .02). CONCLUSIONS: The findings suggest that maternal iron deficiency may be a risk factor for SSDs among offspring. Given that this hypothesis offers the potential for reducing the risk for SSDs, further investigation in independent samples is warranted.

Authors: Insel BJ; Schaefer CA; McKeague IW; Susser ES; Brown AS

Arch Gen Psychiatry. 2008 Oct;65(10):1136-44.

PubMed abstract

Congenital anomalies and early functional impairments in a prospective birth cohort: risk of schizophrenia-spectrum disorder in adulthood

BACKGROUND: Adversities operating over intrauterine life have been associated with risk of schizophrenia, but the biology of resultant developmental perturbation is poorly understood. AIMS: To examine the relationship of congenital anomalies and related functional impairments in infancy to risk of schizophrenia. METHOD: Using the Congenital Anomalies data-set from the Prenatal Determinants of Schizophrenia birth cohort, congenital anomalies and related functional impairments were categorised and related to subsequent risk of schizophrenia-spectrum disorder. RESULTS: The presence of any hypothesis-based congenital anomaly or related functional impairment was associated with a doubling of risk of schizophrenia-spectrum disorder. In contrast, having any other congenital anomaly or related functional impairment was not associated with risk of schizophrenia-spectrum disorder. CONCLUSIONS: These findings constitute evidence for early events, which may result from both genetic predisposition and environmental insults, in the pathogenesis of schizophrenia.

Authors: Waddington JL; Brown AS; Lane A; Schaefer CA; Goetz RR; Bresnahan M; Susser ES

Br J Psychiatry. 2008 Apr;192(4):264-7.

PubMed abstract

Race and risk of schizophrenia in a US birth cohort: another example of health disparity?

BACKGROUND: Immigrant groups in Western Europe have markedly increased rates of schizophrenia. The highest rates are found in ethnic groups that are predominantly black. Separating minority race/ethnicity from immigration in Western Europe is difficult; in the US, these issues can be examined separately. Here we compared rates of schizophrenia between whites and African Americans and evaluated whether the association was mediated by socioeconomic status (SES) of family of origin in a US birth cohort. METHODS: Study subjects were offspring of women enrolled during pregnancy at Alameda County Kaiser Permanente Medical Care Plan clinics (1959-66) in the Child Health and Development Study. For schizophrenia spectrum disorders, 12 094 of the 19 044 live births were followed over 1981-97. The analysis is restricted to cohort members whose mothers identified as African American or white at intake. Stratified proportional hazards regression was the method of analysis; the robustness of findings to missing data bias was assessed using multiple imputation. RESULTS: African Americans were about 3-fold more likely than whites to be diagnosed with schizophrenia [Rate Ratio (RR) = 3.27; 95% confidence interval (CI): 1.71-6.27]. After adjusting for indicators of family SES at birth, the RR was about 2-fold (RR = 1.92; 95% CI: 0.86-4.28). Using multiple imputation in the model including family SES indicators, the RR for race and schizophrenia was strengthened in comparison with the estimate obtained without imputation. CONCLUSION: The data indicate substantially elevated rates of schizophrenia among African Americans in comparison with whites in this birth cohort. The association may have been partly but not wholly mediated by an effect of race on family SES.

Authors: Bresnahan M; Begg MD; Brown A; Schaefer C; Sohler N; Insel B; Vella L; Susser E

Int J Epidemiol. 2007 Aug;36(4):751-8. Epub 2007 Apr 17.

PubMed abstract

The pharmacogenetics research network: from SNP discovery to clinical drug response

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

Authors: Giacomini KM; Schaefer CA; Pharmacogenetics Research Network; et al.

Clin Pharmacol Ther. 2007 Mar;81(3):328-45.

PubMed abstract

Elevated prenatal homocysteine levels as a risk factor for schizophrenia

CONTEXT: Elevated prenatal homocysteine level is a plausible risk factor for schizophrenia because of its partial antagonism of N-methyl-D-aspartate receptors under physiologic glycine concentrations and its association with abnormal placental function and pregnancy complications. OBJECTIVE: We examined whether elevated maternal levels of homocysteine during the third trimester were associated with adult schizophrenia risk. DESIGN: Nested case-control study of a large birth cohort, born from 1959 through 1967 and followed up for schizophrenia from 1981 through 1997. SETTING: Population-based birth cohort and health plan. PARTICIPANTS: Cases (n = 63) were diagnosed with schizophrenia and other spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls (n = 122) belonged to the birth cohort; had not been diagnosed with a schizophrenia spectrum or major affective disorder; and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum samples. MAIN MEASURES: Archived maternal serum samples were assayed for homocysteine levels during pregnancies of cases and matched controls. RESULTS: In a model that tested for a threshold effect of third-trimester homocysteine levels, an elevated homocysteine level was associated with a greater than 2-fold statistically significant increase in schizophrenia risk (odds ratio, 2.39; 95% confidence interval, 1.18-4.81; P = .02). CONCLUSIONS: These findings indicate that elevated third-trimester homocysteine levels may be a risk factor for schizophrenia. Elevated third-trimester homocysteine levels may elevate schizophrenia risk through developmental effects on brain structure and function and/or through subtle damage to the placental vasculature that compromises oxygen delivery to the fetus. If future studies both replicate this association and support a causal link, then the use of folic acid supplementation would merit evaluation as a strategy for prevention of schizophrenia in offspring.

Authors: Brown AS; Bottiglieri T; Schaefer CA; Quesenberry CP Jr; Liu L; Bresnahan M; Susser ES

Arch Gen Psychiatry. 2007 Jan;64(1):31-9.

PubMed abstract

Maternal-fetal blood incompatibility and the risk of schizophrenia in offspring

OBJECTIVE: Predicated on a maternal immune response to paternally inherited foreign fetal blood antigens, we hypothesized that maternal-fetal blood incompatibility increases susceptibility to schizophrenia in the offspring. The relation between schizophrenia and maternal-fetal blood incompatibility, arising from the D antigen of the Rhesus (Rh) and the ABO blood group antigens, was examined in a cohort of live-births. METHOD: The data were drawn from the Prenatal Determinants of Schizophrenia Study, a cohort of births occurring between 1959 and 1967 to women enrolled in a Kaiser Permanente Plan-Northern California Region (KP). Adult offspring belonging to the KP from 1981 to 1997 were followed for the incidence of schizophrenia spectrum disorder (SSD). Cox proportional hazards regression was the primary analytic technique. RESULTS: Among second and later born offspring, the adjusted incidence rate ratio (RR(adj)) of SSD was 1.80 (95% CI=0.71-4.58) for the Rh incompatible offspring compared with the Rh compatible offspring; with the males exhibiting higher rate ratio (RR(adj)=2.37; 95% CI=0.82-6.86) than the females (RR(adj)=0.93 95% CI=0.12-7.01). Among all offspring, the RR(adj) for ABO incompatibility was lower and the elevated rate ratio was similarly limited to the males (RR(adj)=1.68; 95% CI=0.76-3.70). For Rh and/or ABO incompatibility, the RR(adj) was 1.57 (95% CI=0.87-2.82). A statistically significant result was detected only for the male offspring (RR(adj)=2.22; 95% CI=1.10-4.47). CONCLUSION: Although the results should be interpreted with caution given the few events of SSD, the findings extend the line of evidence that maternal-fetal blood incompatibility is a risk factor for schizophrenia spectrum disorder; with the strongest evidence to date implicating that the susceptibility pertains only to male offspring.

Authors: Insel BJ; Brown AS; Bresnahan MA; Schaefer CA; Susser ES

Schizophr Res. 2005 Dec 15;80(2-3):331-42. Epub 2005 Jul 11.

PubMed abstract

Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11-16

Authors: Glatt CE; Carlson E; Taylor TR; Risch N; Reus VI; Schaefer CA

Neuron. 2005 Dec 8;48(5):704-5; author reply 705-6.

PubMed abstract

Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring

OBJECTIVE: The authors examined the relationship between maternal antibody to toxoplasmosis and the risk of schizophrenia and other schizophrenia spectrum disorders in offspring. Toxoplasmosis is known to adversely affect fetal brain development. METHOD: In a nested case-control design of a large birth cohort born between 1959 and 1967, the authors conducted serological assays for Toxoplasma antibody on maternal serum specimens from pregnancies giving rise to 63 cases of schizophrenia and other schizophrenia spectrum disorders and 123 matched comparison subjects. Toxoplasma immunoglobulin (Ig)G antibody was quantified by using the Sabin-Feldman dye test. The Ig titers were classified into three groups: negative (<1:16) (reference), moderate (1:16-1:64), and high (> or =1:128). RESULTS: The adjusted odds ratio of schizophrenia/schizophrenia spectrum disorders for subjects with high maternal Toxoplasma IgG antibody titers was 2.61 (95% confidence interval=1.00-6.82). There was no association between moderate Toxoplasma Ig antibody titers and the risk of schizophrenia/spectrum disorders. CONCLUSIONS: These findings suggest that maternal exposure to toxoplasmosis may be a risk factor for schizophrenia. The findings may be explained by reactivated infection or an effect of the antibody on the developing fetus. Given that toxoplasmosis is a preventable infection, the findings, if replicated, may have implications for reducing the incidence of schizophrenia.

Authors: Brown AS; Schaefer CA; Quesenberry CP Jr; Liu L; Babulas VP; Susser ES

Am J Psychiatry. 2005 Apr;162(4):767-73.

PubMed abstract

Treatment with stimulants among youths in a large California health plan

OBJECTIVE: The aim of this study was to examine the use of stimulants among youths in a large and diverse health plan in California from 1996-2000. METHODS: Computerized pharmacy, outpatient visit, and membership files were used to conduct a population-based analysis of stimulant use among over 500,000 enrollees aged 2-18 years. Annual prevalence rates of stimulant use were estimated by calendar year, age, gender, and geographic area. RESULTS: The annual percentage of continuously enrolled 2- through 18-year-olds receiving at least one prescription for a stimulant rose from 1.86% (95% confidence interval (CI) 1.82-1.90) in 1996 to 1.93% (95% CI, 1.90-1.96) in 2000. An increase was observed only among girls 8 years of age or older and among boys 12 years or older. Use of methylphenidate decreased, whereas use of extended-release amphetamine products increased. Stimulant use was lower and use of other psychotropic drugs was higher among children with visits for attention-deficit/hyperactivity disorder (ADHD) and a coexisting psychiatric disorder than among those seen for ADHD alone. Of the 11,698 children receiving at least one stimulant in 2000, 24% of these children received a single prescription. Approximately 55% of stimulant prescriptions were written by physicians in pediatrics and 45% by physicians in psychiatry. CONCLUSIONS: The prevalence of treatment with stimulants was lower than what generally has been reported in other parts of the United States; it increased by approximately 4% between 1996 and 2000, and was frequently short term or intermittent.

Authors: Habel LA; Schaefer CA; Levine P; Bhat AK; Elliott G

J Child Adolesc Psychopharmacol. 2005 Feb;15(1):62-7.

PubMed abstract

Detection of postpartum depression and anxiety in a large health plan

To determine the prevalence of diagnosed and/or treated postpartum depression and anxiety, records were extracted for 1 year after delivery from databases of outpatient diagnoses and prescriptions, for women in a health maintenance organization who had delivered a child from July 1997 through June 1998. For comparison, telephone interviews were conducted 5 to 9 months after delivery with random samples of women who delivered at 2 facilities from June 1998 through January 1999. Of the women interviewed, 11% met criteria for major depression during the first 4 months postpartum, and an additional 13% met criteria for probable depression at 5 to 9 months postpartum. In contrast 7.0% of the large cohort had a visit or prescription for depression. The 1-year prevalence rate for diagnosed and/or treated anxiety without depression was 3.8%; the rate at time of interview was 14.7%. Overall, less than 33% of women with substantial depression or anxiety symptoms were detected.

Authors: Coates AO; Schaefer CA; Alexander JL

J Behav Health Serv Res. 2004 Apr-Jun;31(2):117-33.

PubMed abstract

Natural variation in human membrane transporter genes reveals evolutionary and functional constraints

Membrane transporters maintain cellular and organismal homeostasis by importing nutrients and exporting toxic compounds. Transporters also play a crucial role in drug response, serving as drug targets and setting drug levels. As part of a pharmacogenetics project, we screened exons and flanking intronic regions for variation in a set of 24 membrane transporter genes (96 kb; 57% coding) in 247 DNA samples from ethnically diverse populations. We identified 680 single nucleotide polymorphisms (SNPs), of which 175 were synonymous and 155 caused amino acid changes, and 29 small insertions and deletions. Amino acid diversity (pi(NS)) in transmembrane domains (TMDs) was significantly lower than in loop domains, suggesting that TMDs have special functional constraints. This difference was especially striking in the ATP-binding cassette superfamily and did not parallel evolutionary conservation: there was little variation in the TMDs, even in evolutionarily unconserved residues. We used allele frequency distribution to evaluate different scoring systems (Grantham, blosum62, SIFT, and evolutionarily conservedevolutionarily unconserved) for their ability to predict which SNPs affect function. Our underlying assumption was that alleles that are functionally deleterious will be selected against and thus under represented at high frequencies and over represented at low frequencies. We found that evolutionary conservation of orthologous sequences, as assessed by evolutionarily conservedevolutionarily unconserved and SIFT, was the best predictor of allele frequency distribution and hence of function. European Americans had an excess of high frequency alleles in comparison to African Americans, consistent with a historic bottleneck. In addition, African Americans exhibited a much higher frequency of population specific medium-frequency alleles than did European Americans.

Authors: Leabman MK; de la Cruz M; Pharmacogenetics Of Membrane Transporters Investigators; et al.

Proc Natl Acad Sci U S A. 2003 May 13;100(10):5896-901. Epub 2003 Apr 28.

PubMed abstract

Maternal prepregnant body mass and risk of schizophrenia in adult offspring

This study examined the relation between maternal prepregnant body mass index (BMI) and development of schizophrenia and schizophrenia spectrum disorders in adult offspring from the Prenatal Determinants of Schizophrenia Study. The study drew on a previously studied cohort of births occurring between 1959 and 1967 to women enrolled in a prepaid health plan. Computerized treatment registries were used to identify possible cases of schizophrenia and spectrum disorders in adult offspring belonging to the health plan from 1981 to 1997. Diagnostic interviews and medical record reviews resulted in diagnosis of 63 cases of schizophrenia and spectrum disorders; these cases and 6,570 unrelated and unaffected cohort members whose mothers also had prepregnancy measures of BMI comprised the sample for analyses. High (> or = 30.0), compared with average (20.0-26.9), maternal prepregnant BMI (kg/m2) was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk [RR] = 2.9; 95% confidence interval [CI] 1.3-6.6), independently of maternal age, parity, race, education, or cigarette smoking during pregnancy. Low (< or = 19.9) maternal BMI was not associated with schizophrenia and spectrum disorders (RR = 1.2; 95% CI 0.64-2.2). Future studies of this cohort will examine factors that may help explain the relationship of high maternal prepregnant BMI with schizophrenia, including nutritional and metabolic factors, toxic exposures, and obstetrical complications.

Authors: Schaefer CA; Brown AS; Wyatt RJ; Kline J; Begg MD; Bresnahan MA; Susser ES

Schizophr Bull. 2000;26(2):275-86.

PubMed abstract

Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study

We sought to examine the relationship between maternal exposure to adult respiratory infections and schizophrenia spectrum disorder (SSD) in the Prenatal Determinants of Schizophrenia (PDS) Study, a large birth cohort investigation. Previous work suggests that second trimester exposure to respiratory infection may be a risk factor for SSD. We therefore examined whether this class of infection was associated with adult SSD. For this purpose, we capitalized on several design advantages of the PDS Study, including a comprehensive, prospective data base on physician-diagnosed infections and a continuous followup in which diagnoses of SSD were made, in the majority, by face-to-face interview. Second trimester exposure to respiratory infections was associated with a significantly increased risk of SSD, adjusting for maternal smoking, education, and race (rate ratio [RR] = 2.13 [1.05-4.35], chi2 = 4.36, df= 1,p = 0.04); no associations were shown for first trimester and third trimester exposure to these respiratory infections. These findings support-and extend-previous studies suggesting that second trimester respiratory infections are risk factors for SSD. This study therefore has implications toward uncovering the etiology of schizophrenia and developing preventive strategies.

Authors: Brown AS; Schaefer CA; Wyatt RJ; Goetz R; Begg MD; Gorman JM; Susser ES

Schizophr Bull. 2000;26(2):287-95.

PubMed abstract

Incidence and cumulative risk of treated schizophrenia in the prenatal determinants of schizophrenia study

The present study uses data from the Prenatal Determinants of Schizophrenia (PDS) Study to derive age- and sex-specific estimates of incidence and cumulative risk for DSM-IV schizophrenia. Although not designed as an incidence study, the PDS Study uses both a well-defined population under continuous followup and DSM-IV diagnoses. The originating cohort was established in Alameda County, California, during 1959-1967 and yielded 12,094 cohort members followed from 1981 to 1997 during the principal ages at risk for schizophrenia. Survival analytic techniques showed that schizophrenia incidence rates per 10,000 person-years for men were 9.4 for ages 15-19; 5.6 for ages 20-24; 3.3 for ages 25-29; and 0.9 for ages 30-34. Schizophrenia incidence rates per 10,000 person-years for women were 1.6 for ages 15-19; 1.3 for ages 20-24; and 4.1 for ages 25-29. The cumulative risk for schizophrenia by age 38 was 0.93 percent for men and 0.35 percent for women. These estimates of incidence rates and risk were higher than those in traditional incidence studies but similar to recent findings in other cohorts. Possible explanations for the apparently high rates of disorder include chance, design effects, and true variation in risk over time and place.

Authors: Bresnahan MA; Brown AS; Schaefer CA; Begg MD; Wyatt RJ; Susser ES

Schizophr Bull. 2000;26(2):297-308.

PubMed abstract

The design of the prenatal determinants of schizophrenia study

This paper describes the Prenatal Determinants of Schizophrenia (PDS) Study; three companion papers report the first results. The PDS Study was designed to study early antecedents of schizophrenia in a birth cohort of 1959-1967 for whom a wealth of archived prenatal data–including maternal sera–was available. Making use of the registries of a health plan into which the cohort was born, we ascertained and then diagnosed 71 cases of schizophrenia and spectrum disorders in the cohort. We describe herein the available prenatal data, the process of case diagnosis, and the strategies used to analyze prenatal determinants of schizophrenia in this cohort. Data are presented that bear on the main sources of potential bias and are important to understanding the strengths and limitations of this unique data set.

Authors: Susser ES; Schaefer CA; Brown AS; Begg MD; Wyatt RJ

Schizophr Bull. 2000;26(2):257-73.

PubMed abstract

Role of a psychiatric outcome study in a large scale quality improvement project

A psychiatric outcomes study that examined caseload attributes, patterns of treatment, and clinical outcomes in 950 adult outpatients was conducted as part of a Quality Improvement (QI) initiative in a large HMO. Patients were assessed pre- and post-treatment with measures of symptomatology (SCL-90) and functioning (SF-36), plus pre-treatment measures of personality disorder, comorbid problems, and sociodemographic variables. Significant improvements in psychological functioning and symptomatology were seen for 39-50% of patients, while 4-11% had significantly worsened. The study not only provided the HMO with useful baseline information on the performance of its psychiatric services, but also provided important lessons in how to conduct outcomes projects relevant to QI efforts. The study should be seen as part of an early effort of a large organization to move from a paradigm of Quality Assurance to one of Quality Improvement in the area of mental health.

Authors: Walter LJ; Schaefer C; Albright L; Parthasarathy S; Hunkeler EM; Westphal J; Williams M

Eval Program Plann. 1999 May;22(2):233-43.

PubMed abstract

Mortality following conjugal bereavement and the effects of a shared environment

​The effect of bereavement on mortality among surviving spouses was examined in a cohort of 12,522 spouse pairs belonging to a prepaid health care plan in northern California. Both spouses were examined and completed a questionnaire between 1964 and 1973, and they were followed for mortality through 1987. Between 1964 and 1987, 1,453 men (12%) and 3,294 women (26%) were bereaved; 440 bereaved men (30%) and 510 women (15%) died during follow-up. Mortality following bereavement was significantly elevated in both men and women after adjusting for age, education, and other predictors of mortality in proportional hazards analyses. The highest relative risks (RRs) of mortality occurred 7-12 months following bereavement. Among women, the RR was 1.9 (95% confidence interval (CI) 1.35-2.71) 7-12 months after bereavement. Among men, the effect of bereavement interacted with prior health status as follows: In men with few health problems, the RR of mortality was 2.12 (95% CI 1.42-3.17); men with many health problems had a RR of 1.56 (95% CI 0.98-2.55) 7-12 months after bereavement. In both men and women, the RR declined after the first year of bereavement but remained above 1.0 for more than 2 years after bereavement. The addition of terms reflecting the influence of the other spouse’s characteristics and behaviors did not alter the RR of mortality, indicating no effect of a shared unfavorable environment on mortality following bereavement.

Authors: Schaefer C; Quesenberry CP Jr; Wi S;

​Am J Epidemiol. 1995 Jun 15;141(12):1142-52.

PubMed abstract

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