Impact of ancestry and common genetic variants on QT interval in African Americans

TY - JOUR

T1 - Impact of ancestry and common genetic variants on QT interval in African Americans

AU - Smith, J Gustav

AU - Avery, Christy L

AU - Evans, Daniel S

AU - Nalls, Michael A

AU - Meng, Yan A

AU - Smith, Erin N

AU - Palmer, Cameron

AU - Tanaka, Toshiko

AU - Mehra, Reena

AU - Butler, Anne M

AU - Young, Taylor

AU - Buxbaum, Sarah G

AU - Kerr, Kathleen F

AU - Berenson, Gerald S

AU - Schnabel, Renate B

AU - Li, Guo

AU - Ellinor, Patrick T

AU - Magnani, Jared W

AU - Chen, Wei

AU - Bis, Joshua C

AU - Curb, J David

AU - Hsueh, Wen-Chi

AU - Rotter, Jerome I

AU - Liu, Yongmei

AU - Newman, Anne B

AU - Limacher, Marian C

AU - North, Kari E

AU - Reiner, Alexander P

AU - Quibrera, P Miguel

AU - Schork, Nicholas J

AU - Singleton, Andrew B

AU - Psaty, Bruce M

AU - Soliman, Elsayed Z

AU - Solomon, Allen J

AU - Srinivasan, Sathanur R

AU - Alonso, Alvaro

AU - Wallace, Robert

AU - Redline, Susan

AU - Zhang, Zhu-Ming

AU - Post, Wendy S

AU - Zonderman, Alan B

AU - Taylor, Herman A

AU - Murray, Sarah S

AU - Ferrucci, Luigi

AU - Arking, Dan E

AU - Evans, Michele K

AU - Fox, Ervin R

AU - Sotoodehnia, Nona

AU - Heckbert, Susan R

AU - Whitsel, Eric A

AU - Newton-Cheh, Christopher

AU - CARe and COGENT consortia

PY - 2012/12

Y1 - 2012/12

N2 - BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

AB - BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

KW - Adult

KW - African Americans/genetics

KW - Aged

KW - Electrocardiography

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genealogy and Heraldry

KW - Genetic Variation

KW - Genome, Human/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1161/CIRCGENETICS.112.962787

DO - 10.1161/CIRCGENETICS.112.962787

M3 - SCORING: Journal article

C2 - 23166209

VL - 5

SP - 647

EP - 655

JO - CIRC-CARDIOVASC GENE

JF - CIRC-CARDIOVASC GENE

SN - 1942-325X

IS - 6

ER -