Dataset Information

Fine Mapping and Identification of BMI Loci in African Americans.

ABSTRACT: Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

SUBMITTER: Gong J

PROVIDER: S-EPMC3791273 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Fine Mapping and Identification of BMI Loci in African Americans.

Gong Jian J Schumacher Fredrick F Lim Unhee U Hindorff Lucia A LA Haessler Jeff J Buyske Steven S Carlson Christopher S CS Rosse Stephanie S Bůžková Petra P Fornage Myriam M Gross Myron M Pankratz Nathan N Pankow James S JS Schreiner Pamela J PJ Cooper Richard R Ehret Georg G Gu C Charles CC Houston Denise D Irvin Marguerite R MR Jackson Rebecca R Kuller Lew L Henderson Brian B Cheng Iona I Wilkens Lynne L Leppert Mark M Lewis Cora E CE Li Rongling R Nguyen Khanh-Dung H KD Goodloe Robert R Farber-Eger Eric E Boston Jonathan J Dilks Holli H HH Ritchie Marylyn D MD Fowke Jay J Pooler Loreall L Graff Misa M Fernandez-Rhodes Lindsay L Cochrane Barbara B Boerwinkle Eric E Kooperberg Charles C Matise Tara C TC Le Marchand Loic L Crawford Dana C DC Haiman Christopher A CA North Kari E KE Peters Ulrike U

American journal of human genetics 20131001 4

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity ...[more]

PMID: 24094743

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Project description:The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P?1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P?1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

Dataset Information

Fine Mapping and Identification of BMI Loci in African Americans.

Publications

Fine Mapping and Identification of BMI Loci in African Americans.

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