Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Ntalla I, Weng LC, Cartwright JH, Hall AW, Sveinbjornsson G, Tucker NR, Choi SH, Chaffin MD, Roselli C, Barnes MR, Mifsud B, Warren HR, Hayward C, Marten J, Cranley JJ, Concas MP, Gasparini P, Boutin T, Kolcic I, Polasek O, Rudan I, Araujo NM, Lima-Costa MF, Ribeiro ALP, Souza RP, Tarazona-Santos E, Giedraitis V, Ingelsson E, Mahajan A, Morris AP, Del Greco M F, Foco L, Gögele M, Hicks AA, Cook JP, Lind L, Lindgren CM, Sundström J, Nelson CP, Riaz MB, Samani NJ, Sinagra G, Ulivi S, Kähönen M, Mishra PP, Mononen N, Nikus K, Caulfield MJ, Dominiczak A, Padmanabhan S, Montasser ME, O'Connell JR, Ryan K, Shuldiner AR, Aeschbacher S, Conen D, Risch L, Thériault S, Hutri-Kähönen N, Lehtimäki T, Lyytikäinen LP, Raitakari OT, Barnes CLK, Campbell H, Joshi PK, Wilson JF, Isaacs A, Kors JA, van Duijn CM, Huang PL, Gudnason V, Harris TB, Launer LJ, Smith AV, Bottinger EP, Loos RJF, Nadkarni GN, Preuss MH, Correa A, Mei H, Wilson J, Meitinger T, Müller-Nurasyid M, Peters A, Waldenberger M, Mangino M, Spector TD, Rienstra M, van de Vegte YJ, van der Harst P, Verweij N, Kääb S, Schramm K, Sinner MF, Strauch K, Cutler MJ, Fatkin D, London B, Olesen M, Roden DM, Benjamin Shoemaker M, Gustav Smith J, Biggs ML, Bis JC, Brody JA, Psaty BM, Rice K, Sotoodehnia N, De Grandi A, Fuchsberger C, Pattaro C, Pramstaller PP, Ford I, Wouter Jukema J, Macfarlane PW, Trompet S, Dörr M, Felix SB, Völker U, Weiss S, Havulinna AS, Jula A, Sääksjärvi K, Salomaa V, Guo X, Heckbert SR, Lin HJ, Rotter JI, Taylor KD, Yao J, de Mutsert R, Maan AC, Mook-Kanamori DO, Noordam R, Cucca F, Ding J, Lakatta EG, Qian Y, Tarasov KV, Levy D, Lin H, Newton-Cheh CH, Lunetta KL, Murray AD, Porteous DJ, Smith BH, Stricker BH, Uitterlinden A, van den Berg ME, Haessler J, Jackson RD, Kooperberg C, Peters U, Reiner AP, Whitsel EA, Alonso A, Arking DE, Boerwinkle E, Ehret GB, Soliman EZ, Avery CL, Gogarten SM, Kerr KF, Laurie CC, Seyerle AA, Stilp A, Assa S, Abdullah Said M, Yldau van der Ende M, Lambiase PD, Orini M, Ramirez J, Van Duijvenboden S, Arnar DO, Gudbjartsson DF, Holm H, Sulem P, Thorleifsson G, Thorolfsdottir RB, Thorsteinsdottir U, Benjamin EJ, Tinker A, Stefansson K, Ellinor PT, Jamshidi Y, Lubitz SA, Munroe PB

Nat Commun 11 (1) 2542 [2020-05-21; online 2020-05-21]

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.

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

PubMed 32439900

DOI 10.1038/s41467-020-15706-x

Crossref 10.1038/s41467-020-15706-x

pii: 10.1038/s41467-020-15706-x
pmc: PMC7242331