Multi-ancestry GWAS of the Electrocardiographic PR Interval Identifies 202 Loci Underlying Cardiac Conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

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References

Cheng S, Keyes M, Larson M, McCabe E, Newton-Cheh C, Levy D . Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. JAMA. 2009; 301(24):2571-7. PMC: 2765917. DOI: 10.1001/jama.2009.888. View

Alonso A, Krijthe B, Aspelund T, Stepas K, Pencina M, Moser C . Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013; 2(2):e000102. PMC: 3647274. DOI: 10.1161/JAHA.112.000102. View

Rasmussen P, Nielsen J, Skov M, Pietersen A, Graff C, Lind B . Electrocardiographic PR Interval Duration and Cardiovascular Risk: Results From the Copenhagen ECG Study. Can J Cardiol. 2017; 33(5):674-681. DOI: 10.1016/j.cjca.2017.02.015. View

Butler A, Yin X, Evans D, Nalls M, Smith E, Tanaka T . Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. Circ Cardiovasc Genet. 2012; 5(6):639-46. PMC: 3560365. DOI: 10.1161/CIRCGENETICS.112.963991. View

Chambers J, Zhao J, Terracciano C, Bezzina C, Zhang W, Kaba R . Genetic variation in SCN10A influences cardiac conduction. Nat Genet. 2010; 42(2):149-52. DOI: 10.1038/ng.516. View

Holm H, Gudbjartsson D, Arnar D, Thorleifsson G, Thorgeirsson G, Stefansdottir H . Several common variants modulate heart rate, PR interval and QRS duration. Nat Genet. 2010; 42(2):117-22. DOI: 10.1038/ng.511. View

Hong K, Lim J, Kim J, Tabara Y, Ueshima H, Miki T . Identification of three novel genetic variations associated with electrocardiographic traits (QRS duration and PR interval) in East Asians. Hum Mol Genet. 2014; 23(24):6659-67. DOI: 10.1093/hmg/ddu374. View

Pfeufer A, van Noord C, Marciante K, Arking D, Larson M, Smith A . Genome-wide association study of PR interval. Nat Genet. 2010; 42(2):153-9. PMC: 2850197. DOI: 10.1038/ng.517. View

Sano M, Kamitsuji S, Kamatani N, Hong K, Han B, Kim Y . Genome-wide association study of electrocardiographic parameters identifies a new association for PR interval and confirms previously reported associations. Hum Mol Genet. 2014; 23(24):6668-76. DOI: 10.1093/hmg/ddu375. View

10.

van Setten J, Brody J, Jamshidi Y, Swenson B, Butler A, Campbell H . PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. Nat Commun. 2018; 9(1):2904. PMC: 6060178. DOI: 10.1038/s41467-018-04766-9. View

11.

Verweij N, Mateo Leach I, van den Boogaard M, Van Veldhuisen D, Christoffels V, Hillege H . Genetic determinants of P wave duration and PR segment. Circ Cardiovasc Genet. 2014; 7(4):475-81. PMC: 4141024. DOI: 10.1161/CIRCGENETICS.113.000373. View

12.

Lin H, van Setten J, Smith A, Bihlmeyer N, Warren H, Brody J . Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circ Genom Precis Med. 2018; 11(5):e002037. PMC: 5951629. DOI: 10.1161/CIRCGEN.117.002037. View

13.

Liu Y, Zhou H, Zhu R, Ding F, Li Y, Cao X . SPSB3 targets SNAIL for degradation in GSK-3β phosphorylation-dependent manner and regulates metastasis. Oncogene. 2017; 37(6):768-776. DOI: 10.1038/onc.2017.370. View

14.

Holm H, Gudbjartsson D, Sulem P, Masson G, Helgadottir H, Zanon C . A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet. 2011; 43(4):316-20. PMC: 3066272. DOI: 10.1038/ng.781. View

15.

Thorolfsdottir R, Sveinbjornsson G, Sulem P, Helgadottir A, Gretarsdottir S, Benonisdottir S . A Missense Variant in PLEC Increases Risk of Atrial Fibrillation. J Am Coll Cardiol. 2017; 70(17):2157-2168. PMC: 5704994. DOI: 10.1016/j.jacc.2017.09.005. View

16.

Schmitt A, Hu M, Jung I, Xu Z, Qiu Y, Tan C . A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome. Cell Rep. 2016; 17(8):2042-2059. PMC: 5478386. DOI: 10.1016/j.celrep.2016.10.061. View

17.

Nielsen J, Fritsche L, Zhou W, Teslovich T, Holmen O, Gustafsson S . Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development. Am J Hum Genet. 2018; 102(1):103-115. PMC: 5777936. DOI: 10.1016/j.ajhg.2017.12.003. View

18.

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

19.

Pers T, Karjalainen J, Chan Y, Westra H, Wood A, Yang J . Biological interpretation of genome-wide association studies using predicted gene functions. Nat Commun. 2015; 6:5890. PMC: 4420238. DOI: 10.1038/ncomms6890. View

20.

Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J . UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015; 12(3):e1001779. PMC: 4380465. DOI: 10.1371/journal.pmed.1001779. View