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Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.

ABSTRACT: Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.

SUBMITTER: Jurgens SJ

PROVIDER: S-EPMC8930703 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.

Jurgens Sean J SJ Choi Seung Hoan SH Morrill Valerie N VN Chaffin Mark M Pirruccello James P JP Halford Jennifer L JL Weng Lu-Chen LC Nauffal Victor V Roselli Carolina C Hall Amelia W AW Oetjens Matthew T MT Lagerman Braxton B vanMaanen David P DP Aragam Krishna G KG Lunetta Kathryn L KL Haggerty Christopher M CM Lubitz Steven A SA Ellinor Patrick T PT

Nature genetics 20220217 3

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Men ...[more]

PMID: 35177841

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Project description:ImportanceHypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis.ObjectiveTo assess the contributions of rare and common genetic variation to risk of HCM in the general population.Design, setting, and participantsThis cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022.ExposuresPathogenic rare variants, common-variant (polygenic) score, and clinical risk factors.Main outcomes and measuresRisk of HCM.ResultsThe primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).Conclusions and relevanceBoth rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.

Dataset Information

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.

Publications

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank.

Similar Datasets

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