QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the…
Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how…
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…
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…
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…
Atopic dermatitis (AD) is more common among African American children. Whether there are racial/ethnic difference among adults with AD and the causes for those disparities are unclear. We sought to examine the relationship between self-reported race/ethnicity and AD and determine…
Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. To…
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…
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…
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.…
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…
Genetic similarity of spouses can reflect factors influencing mate choice, such as physical/behavioral characteristics, and patterns of social endogamy. Spouse correlations for both genetic ancestry and measured traits may impact genotype distributions (Hardy Weinberg and linkage equilibrium), and therefore genetic…
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…
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…
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…
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…
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,…
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…
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…
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…
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…
We report a genome-wide association study (GWAS) and admixture analysis of glaucoma in 12 008 African-American and Hispanic women (age 50-79 years) from the Women's Health Initiative (WHI). Although GWAS of glaucoma have been conducted on several populations, this is…
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…
This study was designed to examine the pattern of familial recurrence of autism spectrum disorder (ASD) in terms of genetic and environmental contributions related to timing of birth. The authors linked California Department of Developmental Services records with state birth…
Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD). To examine stoppage in a large, population-based cohort of families in which a child has received a diagnosis of…
Atrial fibrillation (AF) is the most common arrhythmia in women and is associated with higher rates of stroke and death. Rates of AF are lower in African American subjects compared with European Americans, suggesting European ancestry could contribute to AF…
Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci…
Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it…
Identifying population stratification and genotyping error are important for candidate gene association studies using the Transmission Disequilibrium Test (TDT). Although the TDT retains the prespecified Type I error in the presence of population stratification; the test may have decreased power…
Recent genetic research has led to the identification of a significant number of genes with a major influence on epilepsy, but the genes identified so far affect risk in a very small proportion of patients – primarily those from families…
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…
CONTEXT: Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins. OBJECTIVE: To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared…
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…
Contemporary genetic variation among Latin Americans human groups reflects population migrations shaped by complex historical, social and economic factors. Consequently, admixture patterns may vary by geographic regions ranging from countries to neighborhoods. We examined the geographic variation of admixture across…
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African…
OBJECTIVES: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). BACKGROUND: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of…
Population stratification leads to a predictable phenomenon-a reduction in the number of heterozygotes compared to that calculated assuming Hardy-Weinberg Equilibrium (HWE). We show that population stratification results in another phenomenon-an excess in the proportion of spouse-pairs with the same genotypes…
Noncoding DNA, particularly intronic DNA, harbors important functional elements that affect gene expression and RNA splicing. Yet, it is unclear which specific noncoding sites are essential for gene function and regulation. To identify functional elements in noncoding DNA, we characterized…
BACKGROUND: While spouse correlations have been documented for numerous traits, no prior studies have assessed assortative mating for genetic ancestry in admixed populations. RESULTS: Using 104 ancestry informative markers, we examined spouse correlations in genetic ancestry for Mexican spouse pairs…
CONTEXT: Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on…
Obesity is a heritable trait and a major risk factor for highly prevalent common diseases such as hypertension and type 2 diabetes. Previously we showed that BMI was positively correlated with African ancestry among the African Americans (AAs) in the…
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs…
Blood lipid levels, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), are highly heritable traits and major risk factors for atherosclerotic cardiovascular disease (CVD). Using individual ancestry estimates at marker locations across the genome, we present…
BACKGROUND: Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped…
Migrations to the new world brought together individuals from Europe, Africa and the Americans. Inter-mating between these migrant and indigenous populations led to the subsequent formation of new admixed populations, such as African and Latino Americans. These unprecedented events brought…
A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are…
While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a…
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5…
BACKGROUND: The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in…
Recent studies have used dense markers to examine the human genome in ancestrally homogeneous populations for hallmarks of selection. No genomewide studies have focused on recently admixed groups--populations that have experienced admixing among continentally divided ancestral populations within the past…
BACKGROUND: The two existing estimates of the incidence of primary cervical dystonia were based on observations in relatively ethnically homogeneous populations of European descent. OBJECTIVE: To estimate the minimum incidence of primary cervical dystonia in the multiethnic membership of a…
A GAG deletion in the DYT1 gene is a major cause of early-onset dystonia, but clinical disease expression occurs in only 30% of mutation carriers. To gain insight into genetic factors that may influence penetrance, we evaluated three DYT1 single-nucleotide…
Interferon (IFN)-alpha-based therapy for chronic hepatitis C is effective in fewer than 50% of all treated patients, with a substantially lower response rate in black patients. The goal of this study was to investigate the underlying host transcriptional response associated…
Twin designs, comparing correlations in monozygotic (MZ) versus dizygotic (DZ) twins, have an extensive history. One major confounder in such studies is that MZ twins may share postnatal environmental influences more so than do DZ twins. To avoid such confounding,…
Latinos are the largest minority population in the United States. Although usually classified as a single ethnic group by researchers, Latinos are heterogeneous from cultural, socioeconomic, and genetic perspectives. From a cultural and social perspective, Latinos represent a wide variety…
Identification of genetic variants that contribute to risk of hypertension is challenging. As a complement to linkage and candidate gene association studies, we carried out admixture mapping using genome-scan microsatellite markers among the African American participants in the US National…
We have analyzed genetic data for 326 microsatellite markers that were typed uniformly in a large multiethnic population-based sample of individuals as part of a study of the genetics of hypertension (Family Blood Pressure Program). Subjects identified themselves as belonging…
Human genetic linkage maps are based on rates of recombination across the genome. These rates in humans vary by the sex of the parent from whom alleles are inherited, by chromosomal position, and by genomic features, such as GC content…
Descriptions of human genetic variation given thirty years ago have held up well, considering the substantial accrual of DNA sequence data in the interim. Most importantly, estimates of between-group genetic variation have remained relatively low. Despite the low average level…
Glycogen storage disease type Ia (GSDIa) is a severe autosomal recessive disorder caused by deficiency of the enzyme D-glucose-6-phosphatase (G6Pase). While numerous mutations have been found in cosmopolitan European populations, Ashkenazi Jewish (AJ) patients appear to primarily carry the R83C…
Given the continuing difficulty of identifying genes for complex disorders in a robust, replicable manner, and the extensive resources devoted to this effort, it is becoming increasingly important to analyze the relative benefits of genomics research for public health applications…
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…
The presence of four lysosomal storage diseases (LSDs) at increased frequency in the Ashkenazi Jewish population has suggested to many the operation of natural selection (carrier advantage) as the driving force. We compare LSDs and nonlysosomal storage diseases (NLSDs) in…
The past two decades have witnessed an explosion in the identification, largely by positional cloning, of genes associated with mendelian diseases. The roughly 1,200 genes that have been characterized have clarified our understanding of the molecular basis of human genetic…
The ability to taste the substance phenylthiocarbamide (PTC) has been widely used for genetic and anthropological studies, but genetic studies have produced conflicting results and demonstrated complex inheritance for this trait. We have identified a small region on chromosome 7q…
Autism is considered by many to be the most strongly genetically influenced multifactorial childhood psychiatric disorder. In the absence of any known gene or genes, the main support for this is derived from family and twin studies. Two recent studies…
Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These…
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