Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study

Ervin R. Fox; Solomon K. Musani; Maja Barbalic; Honghuang Lin; Bing Yu; Kofo O. Ogunyankin; Nicholas L. Smith; Abdullah Kutlar; Nicole L. Glazer; Wendy S. Post; Dina N. Paltoo; Daniel L. Dries; Deborah N. Farlow; Christine W. Duarte; Sharon L. Kardia; Kristin J. Meyers; Yan V. Sun; Donna K. Arnett; Amit A. Patki; Jin Sha; Xiangqui Cui; Tandaw E. Samdarshi; Alan D. Penman; Kirsten Bibbins-Domingo; Petra Bůžková; Emelia J. Benjamin; David A. Bluemke; Alanna C. Morrison; Gerardo Heiss; J. Jeffrey Carr; Russell P. Tracy; Thomas H. Mosley; Herman A. Taylor; Bruce M. Psaty; Susan R. Heckbert; Thomas P. Cappola; Ramachandran S. Vasan

doi:10.1161/CIRCGENETICS.111.962365

Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study

Ervin R. Fox, Solomon K. Musani, Maja Barbalic, Honghuang Lin, Bing Yu, Kofo O. Ogunyankin, Nicholas L. Smith, Abdullah Kutlar, Nicole L. Glazer, Wendy S. Post, Dina N. Paltoo, Daniel L. Dries, Deborah N. Farlow, Christine W. Duarte, Sharon L. Kardia, Kristin J. Meyers, Yan V. Sun, Donna K. Arnett, Amit A. Patki, Jin ShaXiangqui Cui, Tandaw E. Samdarshi, Alan D. Penman, Kirsten Bibbins-Domingo, Petra Bůžková, Emelia J. Benjamin, David A. Bluemke, Alanna C. Morrison, Gerardo Heiss, J. Jeffrey Carr, Russell P. Tracy, Thomas H. Mosley, Herman A. Taylor, Bruce M. Psaty, Susan R. Heckbert, Thomas P. Cappola, Ramachandran S. Vasan

Research output: Contribution to journal › Review article › peer-review

41 Scopus citations

Abstract

Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genomewide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genomewide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10-7). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10-7) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10-7) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10-8) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10-7) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

Original language	English (US)
Pages (from-to)	37-46
Number of pages	10
Journal	Circulation: Cardiovascular Genetics
Volume	6
Issue number	1
DOIs	https://doi.org/10.1161/CIRCGENETICS.111.962365
State	Published - Feb 2013
Externally published	Yes

Keywords

Echocardiography
Ethnic
Genome-wide association studies
Left atrium genetics
Left ventricular mass genetics

ASJC Scopus subject areas

Genetics
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1161/CIRCGENETICS.111.962365

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Fox, E. R., Musani, S. K., Barbalic, M., Lin, H., Yu, B., Ogunyankin, K. O., Smith, N. L., Kutlar, A., Glazer, N. L., Post, W. S., Paltoo, D. N., Dries, D. L., Farlow, D. N., Duarte, C. W., Kardia, S. L., Meyers, K. J., Sun, Y. V., Arnett, D. K., Patki, A. A., ... Vasan, R. S. (2013). Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study. Circulation: Cardiovascular Genetics, 6(1), 37-46. https://doi.org/10.1161/CIRCGENETICS.111.962365

Fox, ER, Musani, SK, Barbalic, M, Lin, H, Yu, B, Ogunyankin, KO, Smith, NL, Kutlar, A, Glazer, NL, Post, WS, Paltoo, DN, Dries, DL, Farlow, DN, Duarte, CW, Kardia, SL, Meyers, KJ, Sun, YV, Arnett, DK, Patki, AA, Sha, J, Cui, X, Samdarshi, TE, Penman, AD, Bibbins-Domingo, K, Bůžková, P, Benjamin, EJ, Bluemke, DA, Morrison, AC, Heiss, G, Carr, JJ, Tracy, RP, Mosley, TH, Taylor, HA, Psaty, BM, Heckbert, SR, Cappola, TP & Vasan, RS 2013, 'Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study', Circulation: Cardiovascular Genetics, vol. 6, no. 1, pp. 37-46. https://doi.org/10.1161/CIRCGENETICS.111.962365

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title = "Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study",

abstract = "Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genomewide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genomewide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10-7). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10-7) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10-7) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10-8) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10-7) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.",

keywords = "Echocardiography, Ethnic, Genome-wide association studies, Left atrium genetics, Left ventricular mass genetics",

author = "Fox, {Ervin R.} and Musani, {Solomon K.} and Maja Barbalic and Honghuang Lin and Bing Yu and Ogunyankin, {Kofo O.} and Smith, {Nicholas L.} and Abdullah Kutlar and Glazer, {Nicole L.} and Post, {Wendy S.} and Paltoo, {Dina N.} and Dries, {Daniel L.} and Farlow, {Deborah N.} and Duarte, {Christine W.} and Kardia, {Sharon L.} and Meyers, {Kristin J.} and Sun, {Yan V.} and Arnett, {Donna K.} and Patki, {Amit A.} and Jin Sha and Xiangqui Cui and Samdarshi, {Tandaw E.} and Penman, {Alan D.} and Kirsten Bibbins-Domingo and Petra Bů{\v z}kov{\'a} and Benjamin, {Emelia J.} and Bluemke, {David A.} and Morrison, {Alanna C.} and Gerardo Heiss and Carr, {J. Jeffrey} and Tracy, {Russell P.} and Mosley, {Thomas H.} and Taylor, {Herman A.} and Psaty, {Bruce M.} and Heckbert, {Susan R.} and Cappola, {Thomas P.} and Vasan, {Ramachandran S.}",

year = "2013",

month = feb,

doi = "10.1161/CIRCGENETICS.111.962365",

language = "English (US)",

volume = "6",

pages = "37--46",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "1",

}

TY - JOUR

T1 - Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study

AU - Fox, Ervin R.

AU - Musani, Solomon K.

AU - Barbalic, Maja

AU - Lin, Honghuang

AU - Yu, Bing

AU - Ogunyankin, Kofo O.

AU - Smith, Nicholas L.

AU - Kutlar, Abdullah

AU - Glazer, Nicole L.

AU - Post, Wendy S.

AU - Paltoo, Dina N.

AU - Dries, Daniel L.

AU - Farlow, Deborah N.

AU - Duarte, Christine W.

AU - Kardia, Sharon L.

AU - Meyers, Kristin J.

AU - Sun, Yan V.

AU - Arnett, Donna K.

AU - Patki, Amit A.

AU - Sha, Jin

AU - Cui, Xiangqui

AU - Samdarshi, Tandaw E.

AU - Penman, Alan D.

AU - Bibbins-Domingo, Kirsten

AU - Bůžková, Petra

AU - Benjamin, Emelia J.

AU - Bluemke, David A.

AU - Morrison, Alanna C.

AU - Heiss, Gerardo

AU - Carr, J. Jeffrey

AU - Tracy, Russell P.

AU - Mosley, Thomas H.

AU - Taylor, Herman A.

AU - Psaty, Bruce M.

AU - Heckbert, Susan R.

AU - Cappola, Thomas P.

AU - Vasan, Ramachandran S.

PY - 2013/2

Y1 - 2013/2

N2 - Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genomewide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genomewide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10-7). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10-7) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10-7) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10-8) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10-7) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

AB - Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genomewide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genomewide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10-7). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10-7) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10-7) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10-8) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10-7) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

KW - Echocardiography

KW - Ethnic

KW - Genome-wide association studies

KW - Left atrium genetics

KW - Left ventricular mass genetics

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DO - 10.1161/CIRCGENETICS.111.962365

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SN - 1942-325X

VL - 6

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JO - Circulation: Cardiovascular Genetics

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ER -

Genome-wide association study of cardiac structure and systolic function in African Americans the Candidate gene Association Resource (CARe) study

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