Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts

TY - JOUR

T1 - Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts

AU - Butler, Anne M

AU - Yin, Xiaoyan

AU - Evans, Daniel S

AU - Nalls, Michael A

AU - Smith, Erin N

AU - Tanaka, Toshiko

AU - Li, Guo

AU - Buxbaum, Sarah G

AU - Whitsel, Eric A

AU - Alonso, Alvaro

AU - Arking, Dan E

AU - Benjamin, Emelia J

AU - Berenson, Gerald S

AU - Bis, Josh C

AU - Chen, Wei

AU - Deo, Rajat

AU - Ellinor, Patrick T

AU - Heckbert, Susan R

AU - Heiss, Gerardo

AU - Hsueh, Wen-Chi

AU - Keating, Brendan J

AU - Kerr, Kathleen F

AU - Li, Yun

AU - Limacher, Marian C

AU - Liu, Yongmei

AU - Lubitz, Steven A

AU - Marciante, Kristin D

AU - Mehra, Reena

AU - Meng, Yan A

AU - Newman, Anne B

AU - Newton-Cheh, Christopher

AU - North, Kari E

AU - Palmer, Cameron D

AU - Psaty, Bruce M

AU - Quibrera, P Miguel

AU - Redline, Susan

AU - Reiner, Alex P

AU - Rotter, Jerome I

AU - Schnabel, Renate B

AU - Schork, Nicholas J

AU - Singleton, Andrew B

AU - Smith, J Gustav

AU - Soliman, Elsayed Z

AU - Srinivasan, Sathanur R

AU - Zhang, Zhu-ming

AU - Zonderman, Alan B

AU - Ferrucci, Luigi

AU - Murray, Sarah S

AU - Evans, Michele K

AU - Sotoodehnia, Nona

AU - Magnani, Jared W

AU - Avery, Christy L

PY - 2012/12

Y1 - 2012/12

N2 - 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 ≈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 (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 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<5.0 × 10(-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<5.0 × 10(-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.

AB - 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 ≈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 (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 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<5.0 × 10(-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<5.0 × 10(-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.

KW - Adult

KW - African Americans/genetics

KW - Cohort Studies

KW - Electrocardiography

KW - Female

KW - Genetic Loci/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Meta-Analysis as Topic

KW - Middle Aged

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1161/CIRCGENETICS.112.963991

DO - 10.1161/CIRCGENETICS.112.963991

M3 - SCORING: Journal article

C2 - 23139255

VL - 5

SP - 639

EP - 646

JO - CIRC-CARDIOVASC GENE

JF - CIRC-CARDIOVASC GENE

SN - 1942-325X

IS - 6

ER -