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 Muller-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 LyytikainenHao 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, Jorgen 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, Andre Uitterlinden, Mark Eijgelsheim, Sandosh Padmanabhan, Blair H. Smith, Henry Volzke, Massimo Mangino, Timothy D. Spector, Michiel L. Bots, Marco Perez, Mika Kahonen, 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 Kaab, Ozren Polasek, Pim van der Harst, Susan R. Heckbert, J. Wouter Jukema, Bruno H. Stricker, Caroline Hayward, Marcus Dorr, Yalda Jamshidi, Folkert W. Asselbergs, Charles Kooperberg, Terho Lehtimaki, James G. Wilson, Patrick T. Ellinor, Steven A. Lubitz*, Aaron Isaacs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Web of Science)

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2x10(-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=5.9x10(-11)) and SCN5A (P=1.1x10(-7)) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: 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.
Original languageEnglish
Article numbere002037   
Number of pages11
JournalCirculation: Genomic and Precision Medicine
Volume11
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • atrioventricular node
  • genetic loci
  • genome-wide association study
  • LONG QT SYNDROME
  • GENOME-WIDE ASSOCIATION
  • SUDDEN CARDIAC DEATH
  • ATRIAL-FIBRILLATION
  • DILATED CARDIOMYOPATHY
  • QRS DURATION
  • SCN5A GENE
  • CONDUCTION
  • VARIANTS
  • SCN10A
  • SUSCEPTIBILITY
  • LOCI
  • HERITABILITY
  • MUTATIONS

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