Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project

Lettre, Guillaume; Palmer, Cameron D; Young, Taylor; Ejebe, Kenechi G; Allayee, Hooman; Benjamin, Emelia J; Bennett, Franklyn; Bowden, Donald W; Chakravarti, Aravinda; Dreisbach, Al; Farlow, Deborah N; Folsom, Aaron R; Fornage, Myriam; Forrester, Terrence; Fox, Ervin; Haiman, Christopher A; Hartiala, Jaana; Harris, Tamara B; Hazen, Stanley L; Heckbert, Susan R; Henderson, Brian E; Hirschhorn, Joel N; Keating, Brendan J; Kritchevsky, Stephen B; Larkin, Emma; Li, Mingyao; Rudock, Megan E; McKenzie, Colin A; Meigs, James B; Meng, Yang A; Mosley, Tom H; Newman, Anne B; Newton-Cheh, Christopher H; Paltoo, Dina N; Papanicolaou, George J; Patterson, Nick; Post, Wendy S; Psaty, Bruce M; Qasim, Atif N; Qu, Liming; Rader, Daniel J; Redline, Susan; Reilly, Muredach P; Reiner, Alexander P; Rich, Stephen S; Rotter, Jerome I; Liu, Yongmei; Shrader, Peter; Siscovick, David S; Tang, W H Wilson; Taylor, Herman A; Tracy, Russell P; Vasan, Ramachandran S; Waters, Kevin M; Wilks, Rainford; Wilson, James G; Fabsitz, Richard R; Gabriel, Stacey B; Kathiresan, Sekar; Boerwinkle, Eric

Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project

Guillaume Lettre, Cameron D Palmer, Taylor Young, Kenechi G Ejebe, Hooman Allayee, Emelia J Benjamin, Franklyn Bennett, Donald W Bowden, Aravinda Chakravarti, Al Dreisbach, Deborah N Farlow, Aaron R Folsom, Myriam Fornage, Terrence Forrester, Ervin Fox, Christopher A Haiman, Jaana Hartiala, Tamara B Harris, Stanley L Hazen, Susan R Heckbert, Brian E Henderson, Joel N Hirschhorn, Brendan J Keating, Stephen B Kritchevsky, Emma Larkin, Mingyao Li, Megan E Rudock, Colin A McKenzie, James B Meigs, Yang A Meng, Tom H Mosley, Anne B Newman, Christopher H Newton-Cheh, Dina N Paltoo, George J Papanicolaou, Nick Patterson, Wendy S Post, Bruce M Psaty, Atif N Qasim, Liming Qu, Daniel J Rader, Susan Redline, Muredach P Reilly, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, Yongmei Liu, Peter Shrader, David S Siscovick, W H Wilson Tang, Herman A Taylor, Russell P Tracy, Ramachandran S Vasan, Kevin M Waters, Rainford Wilks, James G Wilson, Richard R Fabsitz, Stacey B Gabriel, Sekar Kathiresan and Eric Boerwinkle

PLOS Genetics, 2011, vol. 7, issue 2, 1-11

Abstract: Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.Author Summary: To date, most large-scale genome-wide association studies (GWAS) carried out to identify risk factors for complex human diseases and traits have focused on population of European ancestry. It is currently unknown whether the same loci associated with complex diseases and traits in Caucasians will replicate in population of African ancestry. Here, we conducted a large GWAS to identify common DNA polymorphisms associated with coronary heart disease (CHD) and its risk factors (type-2 diabetes, hypertension, smoking status, and LDL- and HDL-cholesterol) in 8,090 African Americans as part of the NHLBI Candidate gene Association Resource (CARe) Project. We replicated 17 associations previously reported in Caucasians, suggesting that the same loci carry common DNA sequence variants associated with CHD and its risk factors in Caucasians and African Americans. At five of these 17 loci, we used the different patterns of linkage disequilibrium between populations of European and African ancestry to identify DNA sequence variants more strongly associated with phenotypes than the index SNPs found in Caucasians, suggesting smaller genomic intervals to search for causal alleles. We also used the CARe data to develop new statistical methods to perform association studies in admixed populations. The CARe Project data represent an extraordinary resource to expand our understanding of the genetics of complex diseases and traits in non-European-derived populations.

Date: 2011
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DOI: 10.1371/journal.pgen.1001300

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