Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel.

Telephone-based social health screening by pharmacists in the nonadherent Medicare population.

Unmet social health needs are associated with medication nonadherence. Although pharmacists are well positioned to address medication nonadherence, there is limited experience with screening for and addressing social health needs. To compare the prevalence of social health needs among Medicare patients with higher vs lower social health risk using a predictive model.

Metformin Cessation and Dementia Incidence.

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin.

Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence.

Polygenic Risk Score and Statin Relative Risk Reduction for Primary Prevention of Myocardial Infarction in a Real-World Population.

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 statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort.

UACA locus is associated with breast cancer chemoresistance and survival.

Few germline genetic variants have been robustly linked with breast cancer outcomes. We conducted trans-ethnic meta genome-wide association study (GWAS) of overall survival (OS) in 3973 breast cancer patients from the Pathways Study, one of the largest prospective breast cancer survivor cohorts. A locus spanning the UACA gene, a key regulator of tumor suppressor Par-4, was associated with OS in patients taking Par-4 dependent chemotherapies, including anthracyclines and anti-HER2 therapy, at a genome-wide significance level ([Formula: see text]).

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.

Meta-Analysis of 26 638 Individuals Identifies Two Genetic Loci Associated With Left Ventricular Ejection Fraction.

Background: 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.

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.

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.

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.

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

Objective: To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment.

Methods: 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.

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.

Background: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL.

Methods: 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.

Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol.

Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response.

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

Background: 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.

Methods: 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).

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.

Association of LPA Variants With Aortic Stenosis: A Large-Scale Study Using Diagnostic and Procedural Codes From Electronic Health Records.

Importance: Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established.

Objective: To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS.

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.

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), 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.

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.

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.

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

Unlabelled: 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.

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.