Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Honghuang Lin, Jessica van Setten, Albert V. Smith, Nathan A. Bihlmeyer, Helen R. Warren, Jennifer A. Brody, Farid Radmanesh, Leanne Hall, Niels Grarup, Martina Müller-Nurasyid, Thibaud Boutin, Niek Verweij, Henry J. Lin, Ruifang Li-Gao, Marten E. van den Berg, Jonathan Marten, Stefan Weiss, Bram P. Prins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Hao Mei, Tamara B. Harris, Lenore J. Launer, Man Li, Alvaro Alonso, Elsayed Z. Soliman, John M. Connell, Paul L. Huang, Lu-Chen Weng, Heather S. Jameson, William Hucker, Alan Hanley, Nathan R. Tucker, Yii-Der Ida Chen, Joshua C. Bis, Kenneth M. Rice, Colleen M. Sitlani, Jan A. Kors, Zhijun Xie, Chengping Wen, Jared W. Magnani, Christopher P. Nelson, Jørgen K. Kanters, Moritz F. Sinner, Konstantin Strauch, Annette Peters, Melanie Waldenberger, Thomas Meitinger, Jette Bork-Jensen, Oluf Pedersen, Allan Linneberg, Igor Rudan, Rudolf A. de Boer, Peter van der Meer, Jie Yao, Xiuqing Guo, Kent D. Taylor, Nona Sotoodehnia, Jerome I. Rotter, Dennis O. Mook-Kanamori, Stella Trompet, Fernando Rivadeneira, André Uitterlinden, Mark Eijgelsheim, Sandosh Padmanabhan, Blair H. Smith, Henry Völzke, Stephan B. Felix, Georg Homuth, Uwe Völker, Massimo Mangino, Timothy D. Spector, Michiel L. Bots, Marco Perez, Mika Kähönen, Olli T. Raitakari, Vilmundur Gudnason, Dan E. Arking, Patricia B. Munroe, Bruce M. Psaty, Cornelia M. van Duijn, Emelia J. Benjamin, Jonathan Rosand, Nilesh J. Samani, Torben Hansen, Stefan Kääb, Ozren Polasek, Pim van der Harst, Susan R. Heckbert, J. Wouter Jukema, Bruno H. Stricker, Caroline Hayward, Marcus Dörr, Yalda Jamshidi, Folkert W. Asselbergs, Charles Kooperberg, Terho Lehtimäki, James G. Wilson, Patrick T. Ellinor, Steven A. Lubitz, Aaron Isaacs

Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.