Advanced

Novel Loci Associated With PR Interval in a Genome-Wide Association Study of 10 African American Cohorts

Butler, Anne M.; Yin, Xiaoyan; Evans, Daniel S.; Nalls, Michael A.; Smith, Erin N.; Tanaka, Toshiko; Li, Guo; Buxbaum, Sarah G.; Whitsel, Eric A. and Alonso, Alvaro, et al. (2012) In Circulation: Cardiovascular Genetics 5(6). p.639-646
Abstract
Background-The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results-We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and approximate to 2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was... (More)
Background-The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results-We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and approximate to 2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (lambda range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (lambda: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0x10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0x10-8). Conclusions-This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent. (Circ Cardiovasc Genet. 2012;5:639-646.) (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
electrocardiography, epidemiology, genome-wide association study, PR, interval, single-nucleotide polymorphism genetics
in
Circulation: Cardiovascular Genetics
volume
5
issue
6
pages
639 - 646
publisher
American Heart Association
external identifiers
  • wos:000312774800012
  • scopus:84873918452
ISSN
1942-325X
DOI
10.1161/CIRCGENETICS.112.963991
language
English
LU publication?
yes
id
04493a54-d532-459c-97ca-b04c3958a868 (old id 3512196)
date added to LUP
2013-03-01 07:52:36
date last changed
2017-09-24 03:01:33
@article{04493a54-d532-459c-97ca-b04c3958a868,
  abstract     = {Background-The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results-We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and approximate to 2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (lambda range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (lambda: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P&lt;5.0x10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P&lt;5.0x10-8). Conclusions-This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent. (Circ Cardiovasc Genet. 2012;5:639-646.)},
  author       = {Butler, Anne M. and Yin, Xiaoyan and Evans, Daniel S. and Nalls, Michael A. and Smith, Erin N. and Tanaka, Toshiko and Li, Guo and Buxbaum, Sarah G. and Whitsel, Eric A. and Alonso, Alvaro and Arking, Dan E. and Benjamin, Emelia J. and Berenson, Gerald S. and Bis, Josh C. and Chen, Wei and Deo, Rajat and Ellinor, Patrick T. and Heckbert, Susan R. and Heiss, Gerardo and Hsueh, Wen-Chi and Keating, Brendan J. and Kerr, Kathleen F. and Li, Yun and Limacher, Marian C. and Liu, Yongmei and Lubitz, Steven A. and Marciante, Kristin D. and Mehra, Reena and Meng, Yan A. and Newman, Anne B. and Newton-Cheh, Christopher and North, Kari E. and Palmer, Cameron D. and Psaty, Bruce M. and Quibrera, P. Miguel and Redline, Susan and Reiner, Alex P. and Rotter, Jerome I. and Schnabel, Renate B. and Schork, Nicholas J. and Singleton, Andrew B. and Smith, Gustav and Soliman, Elsayed Z. and Srinivasan, Sathanur R. and Zhang, Zhu-ming and Zonderman, Alan B. and Ferrucci, Luigi and Murray, Sarah S. and Evans, Michele K. and Sotoodehnia, Nona and Magnani, Jared W. and Avery, Christy L.},
  issn         = {1942-325X},
  keyword      = {electrocardiography,epidemiology,genome-wide association study,PR,interval,single-nucleotide polymorphism genetics},
  language     = {eng},
  number       = {6},
  pages        = {639--646},
  publisher    = {American Heart Association},
  series       = {Circulation: Cardiovascular Genetics},
  title        = {Novel Loci Associated With PR Interval in a Genome-Wide Association Study of 10 African American Cohorts},
  url          = {http://dx.doi.org/10.1161/CIRCGENETICS.112.963991},
  volume       = {5},
  year         = {2012},
}