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

Anne M. Butler; Xiaoyan Yin; Daniel S. Evans; Michael A. Nalls; Erin N. Smith; Toshiko Tanaka; Guo Li; Sarah G. Buxbaum; Eric A. Whitsel; Alvaro Alonso; Dan E. Arking; Emelia J. Benjamin; Gerald S. Berenson; Josh C. Bis; Wei Chen; Rajat Deo; Patrick T. Ellinor; Susan R. Heckbert; Gerardo Heiss; Wen Chi Hsueh; Brendan J. Keating; Kathleen F. Kerr; Yun Li; Marian C. Limacher; Yongmei Liu; Steven A. Lubitz; Kristin D. Marciante; Reena Mehra; Yan A. Meng; Anne B. Newman; Christopher Newton-Cheh; Kari E. North; Cameron D. Palmer; Bruce M. Psaty; P. Miguel Quibrera; Susan Redline; Alex P. Reiner; Jerome I. Rotter; Renate B. Schnabel; Nicholas J. Schork; Andrew B. Singleton; J. Gustav Smith; Elsayed Z. Soliman; Sathanur R. Srinivasan; Zhu Ming Zhang; Alan B. Zonderman; Luigi Ferrucci; Sarah S. Murray; Michele K. Evans; Nona Sotoodehnia; Jared W. Magnani; Christy L. Avery

doi:10.1161/CIRCGENETICS.112.963991

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

Anne M. Butler, Xiaoyan Yin, Daniel S. Evans, Michael A. Nalls, Erin N. Smith, Toshiko Tanaka, Guo Li, Sarah G. Buxbaum, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Emelia J. Benjamin, Gerald S. Berenson, Josh C. Bis, Wei Chen, Rajat Deo, Patrick T. Ellinor, Susan R. Heckbert, Gerardo Heiss, Wen Chi HsuehBrendan J. Keating, Kathleen F. Kerr, Yun Li, Marian C. Limacher, Yongmei Liu, Steven A. Lubitz, Kristin D. Marciante, Reena Mehra, Yan A. Meng, Anne B. Newman, Christopher Newton-Cheh, Kari E. North, Cameron D. Palmer, Bruce M. Psaty, P. Miguel Quibrera, Susan Redline, Alex P. Reiner, Jerome I. Rotter, Renate B. Schnabel, Nicholas J. Schork, Andrew B. Singleton, J. Gustav Smith, Elsayed Z. Soliman, Sathanur R. Srinivasan, Zhu Ming Zhang, Alan B. Zonderman, Luigi Ferrucci, Sarah S. Murray, Michele K. Evans, Nona Sotoodehnia, Jared W. Magnani, Christy L. Avery

Epidemiology

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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 ̃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.

Original language	English (US)
Pages (from-to)	639-646
Number of pages	8
Journal	Circulation: Cardiovascular Genetics
Volume	5
Issue number	6
DOIs	https://doi.org/10.1161/CIRCGENETICS.112.963991
State	Published - Dec 2012

Keywords

Electrocardiography
Epidemiology
Genome-wide association study
PR interval
Single-nucleotide polymorphism genetics

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Butler, A. M., Yin, X., Evans, D. S., Nalls, M. A., Smith, E. N., Tanaka, T., Li, G., Buxbaum, S. G., Whitsel, E. A., Alonso, A., Arking, D. E., Benjamin, E. J., Berenson, G. S., Bis, J. C., Chen, W., Deo, R., Ellinor, P. T., Heckbert, S. R., Heiss, G., ... Avery, C. L. (2012). Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. Circulation: Cardiovascular Genetics, 5(6), 639-646. https://doi.org/10.1161/CIRCGENETICS.112.963991

Butler, AM, Yin, X, Evans, DS, Nalls, MA, Smith, EN, Tanaka, T, Li, G, Buxbaum, SG, Whitsel, EA, Alonso, A, Arking, DE, Benjamin, EJ, Berenson, GS, Bis, JC, Chen, W, Deo, R, Ellinor, PT, Heckbert, SR, Heiss, G, Hsueh, WC, Keating, BJ, Kerr, KF, Li, Y, Limacher, MC, Liu, Y, Lubitz, SA, Marciante, KD, Mehra, R, Meng, YA, Newman, AB, Newton-Cheh, C, North, KE, Palmer, CD, Psaty, BM, Quibrera, PM, Redline, S, Reiner, AP, Rotter, JI, Schnabel, RB, Schork, NJ, Singleton, AB, Smith, JG, Soliman, EZ, Srinivasan, SR, Zhang, ZM, Zonderman, AB, Ferrucci, L, Murray, SS, Evans, MK, Sotoodehnia, N, Magnani, JW & Avery, CL 2012, 'Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts', Circulation: Cardiovascular Genetics, vol. 5, no. 6, pp. 639-646. https://doi.org/10.1161/CIRCGENETICS.112.963991

@article{488cfdaf963741afbfe93923e60f359e,

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

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{\~ }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.",

keywords = "Electrocardiography, Epidemiology, Genome-wide association study, PR interval, Single-nucleotide polymorphism genetics",

author = "Butler, {Anne M.} and Xiaoyan Yin and Evans, {Daniel S.} and Nalls, {Michael A.} and Smith, {Erin N.} and Toshiko Tanaka and Guo Li and Buxbaum, {Sarah G.} and Whitsel, {Eric A.} and Alvaro Alonso and Arking, {Dan E.} and Benjamin, {Emelia J.} and Berenson, {Gerald S.} and Bis, {Josh C.} and Wei Chen and Rajat Deo and Ellinor, {Patrick T.} and Heckbert, {Susan R.} and Gerardo Heiss and Hsueh, {Wen Chi} and Keating, {Brendan J.} and Kerr, {Kathleen F.} and Yun Li and Limacher, {Marian C.} and Yongmei Liu and Lubitz, {Steven A.} and Marciante, {Kristin D.} and Reena Mehra and Meng, {Yan A.} and Newman, {Anne B.} and Christopher Newton-Cheh and North, {Kari E.} and Palmer, {Cameron D.} and Psaty, {Bruce M.} and Quibrera, {P. Miguel} and Susan Redline and Reiner, {Alex P.} and Rotter, {Jerome I.} and Schnabel, {Renate B.} and Schork, {Nicholas J.} and Singleton, {Andrew B.} and Smith, {J. Gustav} and Soliman, {Elsayed Z.} and Srinivasan, {Sathanur R.} and Zhang, {Zhu Ming} and Zonderman, {Alan B.} and Luigi Ferrucci and Murray, {Sarah S.} and Evans, {Michele K.} and Nona Sotoodehnia and Magnani, {Jared W.} and Avery, {Christy L.}",

year = "2012",

month = dec,

doi = "10.1161/CIRCGENETICS.112.963991",

language = "English (US)",

volume = "5",

pages = "639--646",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "6",

}

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 - Electrocardiography

KW - Epidemiology

KW - Genome-wide association study

KW - PR interval

KW - Single-nucleotide polymorphism genetics

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U2 - 10.1161/CIRCGENETICS.112.963991

DO - 10.1161/CIRCGENETICS.112.963991

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AN - SCOPUS:84873918452

SN - 1942-325X

VL - 5

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JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

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ER -

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

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