Analysis of Rare Genetic Variation Underlying Cardiometabolic Diseases and Traits Among 200,000 Individuals in the UK Biobank

Overview

Journal Nat Genet

Specialty Genetics

Date 2022 Feb 18

PMID 35177841

Authors

Sean J Jurgens

Seung Hoan Choi

Valerie N Morrill

Mark Chaffin

James P Pirruccello

Jennifer L Halford

Lu-Chen Weng

Victor Nauffal

Carolina Roselli

Amelia W Hall

Matthew T Oetjens

Braxton Lagerman

David P vanMaanen

Krishna G Aragam

Kathryn L Lunetta

Christopher M Haggerty

Steven A Lubitz

Patrick T Ellinor

Affiliations

Soon will be listed here.

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.

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References

Locke A, Kahali B, Berndt S, Justice A, Pers T, Day F . Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015; 518(7538):197-206. PMC: 4382211. DOI: 10.1038/nature14177. View

Roselli C, Chaffin M, Weng L, Aeschbacher S, Ahlberg G, Albert C . Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet. 2018; 50(9):1225-1233. PMC: 6136836. DOI: 10.1038/s41588-018-0133-9. View

Shah S, Henry A, Roselli C, Lin H, Sveinbjornsson G, Fatemifar G . Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun. 2020; 11(1):163. PMC: 6952380. DOI: 10.1038/s41467-019-13690-5. View

Klarin D, Damrauer S, Cho K, Sun Y, Teslovich T, Honerlaw J . Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet. 2018; 50(11):1514-1523. PMC: 6521726. DOI: 10.1038/s41588-018-0222-9. View

Pirruccello J, Bick A, Wang M, Chaffin M, Friedman S, Yao J . Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy. Nat Commun. 2020; 11(1):2254. PMC: 7206184. DOI: 10.1038/s41467-020-15823-7. View

Ntalla I, Weng L, Cartwright J, Hall A, Sveinbjornsson G, Tucker N . Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. Nat Commun. 2020; 11(1):2542. PMC: 7242331. DOI: 10.1038/s41467-020-15706-x. View

Vujkovic M, Keaton J, Lynch J, Miller D, Zhou J, Tcheandjieu C . Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet. 2020; 52(7):680-691. PMC: 7343592. DOI: 10.1038/s41588-020-0637-y. View

Carrier L, Hengstenberg C, Beckmann J, Guicheney P, Dufour C, Bercovici J . Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11. Nat Genet. 1993; 4(3):311-3. DOI: 10.1038/ng0793-311. View

Ahlberg G, Refsgaard L, Lundegaard P, Andreasen L, Ranthe M, Linscheid N . Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nat Commun. 2018; 9(1):4316. PMC: 6193003. DOI: 10.1038/s41467-018-06618-y. View

10.

Keating M, Atkinson D, Dunn C, Timothy K, Vincent G, Leppert M . Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991; 252(5006):704-6. DOI: 10.1126/science.1673802. View

11.

Gerull B, Heuser A, Wichter T, Paul M, Basson C, McDermott D . Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004; 36(11):1162-4. DOI: 10.1038/ng1461. View

12.

Do R, Stitziel N, Won H, Jorgensen A, Duga S, Merlini P . Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2014; 518(7537):102-6. PMC: 4319990. DOI: 10.1038/nature13917. View

13.

Flannick J, Mercader J, Fuchsberger C, Udler M, Mahajan A, Wessel J . Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019; 570(7759):71-76. PMC: 6699738. DOI: 10.1038/s41586-019-1231-2. View

14.

Van Hout C, Tachmazidou I, Backman J, Hoffman J, Liu D, Pandey A . Exome sequencing and characterization of 49,960 individuals in the UK Biobank. Nature. 2020; 586(7831):749-756. PMC: 7759458. DOI: 10.1038/s41586-020-2853-0. View

15.

Cirulli E, White S, Read R, Elhanan G, Metcalf W, Tanudjaja F . Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts. Nat Commun. 2020; 11(1):542. PMC: 6987107. DOI: 10.1038/s41467-020-14288-y. View

16.

Cohen J, Boerwinkle E, Mosley Jr T, Hobbs H . Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354(12):1264-72. DOI: 10.1056/NEJMoa054013. View

17.

Lambert G, Sjouke B, Choque B, Kastelein J, Hovingh G . The PCSK9 decade. J Lipid Res. 2012; 53(12):2515-24. PMC: 3494258. DOI: 10.1194/jlr.R026658. View

18.

Wang Y, Liu Z . PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDLCholesterol. Mini Rev Med Chem. 2018; 19(2):165-176. DOI: 10.2174/1389557518666180423111442. View

19.

Choi S, Jurgens S, Weng L, Pirruccello J, Roselli C, Chaffin M . Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank. Circ Res. 2019; 126(2):200-209. PMC: 7007701. DOI: 10.1161/CIRCRESAHA.119.315686. View

20.

Szustakowski J, Balasubramanian S, Kvikstad E, Khalid S, Bronson P, Sasson A . Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat Genet. 2021; 53(7):942-948. DOI: 10.1038/s41588-021-00885-0. View