Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval
Authors: Lin Honghuang , van Setten Jessica , Smith Albert V. , Bihlmeyer Nathan A. , Warren Helen R. , Brody Jennifer A. , Radmanesh Farid , Hall Leanne , Grarup Niels , Müller-Nurasyid Martina , Boutin Thibaud , Verweij Niek , Lin Henry J. , Li-Gao Ruifang , van den Berg Marten E. , Marten Jonathan , Weiss Stefan , Prins Bram P. , Haessler Jeffrey , Lyytikäinen Leo-Pekka , Mei Hao , Harris Tamara B. , Launer Lenore J. , Li Man , Alonso Alvaro , Soliman Elsayed Z. , Connell John M. , Huang Paul L. , Weng Lu-Chen , Jameson Heather S. , Hucker William , Hanley Alan , Tucker Nathan R. , Chen Yii-Der Ida , Bis Joshua C. , Rice Kenneth M. , Sitlani Colleen M. , Kors Jan A. , Xie Zhijun , Wen Chengping , Magnani Jared W. , Nelson Christopher P. , Kanters Jørgen K. , Sinner Moritz F. , Strauch Konstantin , Peters Annette , Waldenberger Melanie , Meitinger Thomas , Bork-Jensen Jette , Pedersen Oluf , Linneberg Allan , Rudan Igor , de Boer Rudolf A. , van der Meer Peter , Yao Jie , Guo Xiuqing , Taylor Kent D. , Sotoodehnia Nona , Rotter Jerome I. , Mook-Kanamori Dennis O. , Trompet Stella , Rivadeneira Fernando , Uitterlinden André , Eijgelsheim Mark , Padmanabhan Sandosh , Smith Blair H. , Völzke Henry , Felix Stephan B. , Homuth Georg , Völker Uwe , Mangino Massimo , Spector Timothy D. , Bots Michiel L. , Perez Marco , Kähönen Mika , Raitakari Olli T. , Gudnason Vilmundur , Arking Dan E. , Munroe Patricia B. , Psaty Bruce M. , van Duijn Cornelia M. , Benjamin Emelia J. , Rosand Jonathan , Samani Nilesh J. , Hansen Torben , Kääb Stefan , Polasek Ozren , van der Harst Pim , Heckbert Susan R. , Jukema J. Wouter , Stricker Bruno H. , Hayward Caroline , Dörr Marcus , Jamshidi Yalda , Asselbergs Folkert W. , Kooperberg Charles , Lehtimäki Terho , Wilson James G. , Ellinor Patrick T. , Lubitz Steven A. , Isaacs Aaron 
Published: October 2018

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
<1.2×10
−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.

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.