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…
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. This proposal aims to bring together the largest…
This study will apply a targeted metabolomics approach to the prediction of gestational diabetes from a single blood sample collected in the first trimester of pregnancy and stored for the Research Program on Genes, Environment and Health pregnancy cohort study,…
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,…
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,…
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.…
This study will apply a targeted metabolomics approach to the prediction of gestational diabetes mellitus (GDM) from a single blood sample collected in the first trimester of pregnancy and stored for the Research Program on Genes, Environment and Health (RPGEH)…
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…
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…
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…
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…
Cataract is a leading cause of blindness and a major cause of impaired vision worldwide. The overall objective of this study is to better understand the role of genetic and non-genetic factors and causal mechanisms underlying the etiology of cataract…
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…
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…
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…
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…
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…
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…
Bariatric surgery is currently the most effective long-term treatment for severe obesity. However, inter-individual variability in surgery outcomes has been observed, particularly in relation to postoperative weight loss. This study aims to assess the contribution of genetic and non-genetic factors…
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…
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,…
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…
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…
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…
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…
This study, being done with a parallel effort at UCSF, will focus on how bipolar disease is related to Parkinson's disease. We will look within the KPNC membership data, as well as focusing on a specific KP study population of…
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…
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…
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…
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…
Hidradenitis suppurativa (also named: acne inversa) is a chronic inflammatory skin condition that causes painful lumps to form under the skin usually in areas where skin rubs together such as in the armpits, groin, buttocks and under breasts. The overall…
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…
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…
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,…
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…
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…
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…
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…
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…
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…
The study will assess the effects of statin treatment on risk of Alzheimer's disease and related dementias, controlling for potential confounding and examining potential mediating factors among Kaiser Permanente Northern California members during the years 1996 to 2020. A second…
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
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…
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,…
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…
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…
This study, along with a parallel effort at the University of California, San Francisco, will focus on the relationship between bipolar disease and Parkinson's disease.
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…
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…
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…
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…
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)…
The goal of this proposal is to identify genetic loci that affect the risk of keratinocyte carcinoma, examine how environmental risk factors influence genetic risk, and determine whether these loci act to influence the risk of basal cell carcinoma, squamous…
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…
This study brings together investigators from around the world to carry out a genetics study of severe major depressive disorder (MDD) treated with electroconvulsive therapy (ECT). The National Network of Depression Centers and allied centers in the U.S. will carry…
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…
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…
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…
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…
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…
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…
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…
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…
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…
This study considers the extent to which immigration history, social factors, cardiometabolic health, and genetic factors contribute to heterogeneity in dementia incidence between Asian American subgroups and between Asian Americans and whites.
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…
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…
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…
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…
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…
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,…
The goal of this project is 1) to collect longitudinal measures of cognitive function, quality of life, and physical disability on a multi-ethnic sample of 3,000 individuals with multiple sclerosis (MS), using a web-based interface, Clinical and Longitudinal Information Collection…
Observational studies should have a core role in justifying and guiding the development of randomized controlled trials, but to date observational research and trials on Alzheimer’s disease prevention are not closely aligned. Observational and randomized studies nearly always answer different…
The goal of this project is to investigate the effects of genetic polymorphisms in the KIR and HLA genes on psoriasis and psoriatic arthritis.
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…
Cardiotoxicity of commonly prescribed medications, typically assessed by electrocardiographic features such as prolongation of the QT interval, has regulatory effects and is associated with potentially fatal outcomes. This project aims to advance understanding of the genetic basis for drug cardiotoxicity…
This study will utilize the Pregnancy Cohort from the Kaiser Permanente Northern California Research Program on Genes, Environment and Health to characterize the maternal immune profile over pregnancy and evaluate whether there are specific longitudinal patterns that are associated with…
This project expands a consortium of studies examining germline genetic mutations in breast cancer risk in Latinas. It builds on a study that will include approximately 550 Latina women with breast cancer in the Pathways Study; genetic data from Latina…
The objective of this project is to investigate the genetic mechanisms that drive the development of abdominal hernias. This study has three major aims: 1) to investigate the shared and individual genetic risks of different types of abdominal hernia, 2)…
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,…
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…
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…
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)…
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)…
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…
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…
The International Bipolar Sequencing Consortium brings together whole-genome and exome sequence data from multiple case-control and family studies of bipolar disorder for the purpose of investigating the genetic architecture of this condition. Data from multiple institutions and studies will be…
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…
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…
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…
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.…
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…
The focus of this project is to examine the role of known genetic risk factors for age-related macular degeneration in African American subjects through whole-genome-sequencing of samples from the Research Program on Genes, Environment and Health collection.
This study aims to perform an internally validated genome-wide association study of actinic keratoses (AKs) in a group of patients in the Research Program on Genes, Environment and Health (RPGEH) known as the Genetic Epidemiology Research on Aging cohort. Investigators…
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.…
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…
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…
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…
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…
The specific aims of this study are to: 1) Determine whether refractive error predicts the development of glaucoma due to direct effects or shared etiology, or both, by conducting a series of genetic analyses of the two conditions; and 2)…
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…
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.…
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…
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…
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)…
Cognitive impairment, physical disability and progressive disease are common but understudied clinical outcomes that substantially impact quality of life for individuals with multiple sclerosis (MS). Systematic assessment of cognitive function, disability and progression is neither routinely performed, nor results captured…
The aims of this study are: 1) To build a comprehensive risk-prediction model for colorectal cancer and advanced adenoma in 45,000 colorectal tumors and 45,000 controls based on existing common and rare genome-wide genetic variants, demographic characteristics, and lifestyle and…
This Multi-PI grant (H. Wessells, UW & S. Van Den Eeden KPNC) will 1) develop phenotyping algorithms, 2) examine genetic factors that affect risk, and 3) assess if these factors differentially affect subgroups (e.g., diabetic men, etc.). The study will…
We will use the RPGEH GERA cohort to investigate associations of genetic variation (SNP genotypes) with several related conditions, including congestive heart failure, chronic kidney disease, and possibly related phenotypes. Our first objective will be to replicate findings of association…
The primary goal of the study is to confirm that the pre-specified Genomic Prostate Score (GPS) from biopsy tumor tissue predicts metastatic recurrence (MR) in patients diagnosed with localized prostate cancer and treated with radical prostatectomy. Prostate cancer-specific death (PCSD)…
Cutaneous squamous cell carcinoma (SCC) is the second most common cancer among people of European ancestry. The primary risk factor for SCC is sun exposure, but genetics also has a substantial role. To date, no published genome-wide association studies have…
This is the Administrative Coordination Hub for the Pharmacogenomics Research Network (PGRN). The main areas of responsibility include meetings support, communications and coordination of nascent network collaborations.
Understanding similarities among phenotypically distinct cancers could provide insight into biological basis of disease and suggest treatment overlap among patients with seemingly distinct cancers. We will evaluate this by undertaking a genome-wide association study (GWAS) across all major cancers types…
The aim of this project is to foster collaborative research projects that employ the data resources of the Kaiser Permanente Research Program on Genes, Environment and Health by providing support for enhancement of the informatics and analytic infrastructure.
More than 25% of individuals over age 65 and 50% of individuals over age 80 suffer from varying levels of age-related hearing impairment (AHRI), and adults are losing hearing at earlier ages than in the past. There is strong evidence…
The goal of the study is to perform a retrospective study to evaluate biomarkers predictive of aggressive disease using Florescence In Situ Hybridization (FISH) among men with histologically confirmed, clinically localized disease (T1c- T2c) under Active Surveillance (AS).
The goal of this project is to investigate the role of ABCG2 in the disposition and anti-hyperuricemic effects of allopurinol.
The KP Research Bank aims to recruit 280,000 members (200,000 in the general cohort, 30,000 in the cancer cohort, and 50,000 in the pregnancy cohort) total across all regions, to increase the overall Biobank collection to 500,000 (410,000 in the…
Blood cell traits, including red blood cell count (RBC), hemoglobin, white blood cell count (WBC) and platelet count, are important intermediate clinical phenotypes for a variety of cardiovascular, hematologic, oncogenic, immunologic and infectious diseases. The goal of this project is…
Large, clinically well-characterized, longitudinally followed and population-representative patient cohorts are needed to advance the understanding of MS disease progression/disability and cognitive decline, and to translate findings to clinical care. The overall goal of this study is to develop a web-based…
The goal of this project is to identify new genes underlying pediatric cholestasis.
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.…
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…
The aims of this application are to: (1) develop an Exploratory Center of Excellence in ethical, legal, and social implications (ELSI) Research (CEER) focused on translating genomic research into clinical care; (2) develop multi-institutional collaborations and partnerships with diverse communities…
Mammographic density (MD) is one of the strongest known risk factors for breast cancer. Our primary goal is to identify novel genes for MD by conducting a genome-wide association study (GWAS) in 30,000 Caucasian women participating in KPNC's Research Program…
The aims of this application are to: (1) develop an Exploratory Center of Excellence in ethical, legal, and social implications (ELSI) Research (CEER) focused on translating genomic research into clinical care; (2) develop multi-institutional collaborations and partnerships with diverse communities…
The goal of the study is to examine potential gene X environment interactions in relation to risk and progression of multiple sclerosis (MS) in a 2,400-person case control dataset. The study will examine family and self-history of other autoimmune disorders,…
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…
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,…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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,…
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…
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…
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…
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…
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…
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…
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…
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)…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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.…
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…
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…
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…
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…
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…
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…
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…
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.…
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…
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…
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…
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…
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:…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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.…
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…
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)…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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…
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,…
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