TY - JOUR

T1 - Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

AU - Lin, Honghuang

AU - van Setten, Jessica

AU - Smith, Albert V

AU - Bihlmeyer, Nathan A

AU - Warren, Helen R

AU - Brody, Jennifer A

AU - Radmanesh, Farid

AU - Hall, Leanne

AU - Grarup, Niels

AU - Müller-Nurasyid, Martina

AU - Boutin, Thibaud

AU - Verweij, Niek

AU - Lin, Henry J

AU - Li-Gao, Ruifang

AU - van den Berg, Marten E

AU - Marten, Jonathan

AU - Weiss, Stefan

AU - Prins, Bram P

AU - Haessler, Jeffrey

AU - Lyytikäinen, Leo-Pekka

AU - Mei, Hao

AU - Harris, Tamara B

AU - Launer, Lenore J

AU - Li, Man

AU - Alonso, Alvaro

AU - Soliman, Elsayed Z

AU - Connell, John M

AU - Huang, Paul L

AU - Weng, Lu-Chen

AU - Jameson, Heather S

AU - Hucker, William

AU - Hanley, Alan

AU - Tucker, Nathan R

AU - Chen, Yii-Der Ida

AU - Bis, Joshua C

AU - Rice, Kenneth M

AU - Sitlani, Colleen M

AU - Kors, Jan A

AU - Xie, Zhijun

AU - Wen, Chengping

AU - Magnani, Jared W

AU - Nelson, Christopher P

AU - Kanters, Jørgen K.

AU - Sinner, Moritz F

AU - Strauch, Konstantin

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Meitinger, Thomas

AU - Bork-Jensen, Jette

AU - Pedersen, Oluf

AU - Linneberg, Allan

AU - Rudan, Igor

AU - de Boer, Rudolf A

AU - van der Meer, Peter

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Taylor, Kent D

AU - Sotoodehnia, Nona

AU - Rotter, Jerome I

AU - Mook-Kanamori, Dennis O

AU - Trompet, Stella

AU - Rivadeneira, Fernando

AU - Uitterlinden, André

AU - Eijgelsheim, Mark

AU - Padmanabhan, Sandosh

AU - Smith, Blair H

AU - Völzke, Henry

AU - Felix, Stephan B

AU - Homuth, Georg

AU - Völker, Uwe

AU - Mangino, Massimo

AU - Spector, Timothy D

AU - Bots, Michiel L

AU - Perez, Marco

AU - Kähönen, Mika

AU - Raitakari, Olli T

AU - Gudnason, Vilmundur

AU - Arking, Dan E

AU - Munroe, Patricia B

AU - Psaty, Bruce M

AU - van Duijn, Cornelia M

AU - Benjamin, Emelia J

AU - Rosand, Jonathan

AU - Samani, Nilesh J

AU - Hansen, Torben

AU - Kääb, Stefan

AU - Polasek, Ozren

AU - van der Harst, Pim

AU - Heckbert, Susan R

AU - Jukema, J Wouter

AU - Stricker, Bruno H

AU - Hayward, Caroline

AU - Dörr, Marcus

AU - Jamshidi, Yalda

AU - Asselbergs, Folkert W

AU - Kooperberg, Charles

AU - Lehtimäki, Terho

AU - Wilson, James G

AU - Ellinor, Patrick T

AU - Lubitz, Steven A

AU - Isaacs, Aaron

N1 - © 2018 American Heart Association, Inc.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1161/CIRCGEN.117.002037

DO - 10.1161/CIRCGEN.117.002037

M3 - Journal article

C2 - 29748316

VL - 11

SP - 1

EP - 11

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 2574-8300

IS - 5

M1 - e002037

ER -