Abstract
BackgroundGenome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women’s Health Initiative (WHI).ResultsWe identified a genome-wide significant association in MESA Hispanics—rs12253976 in KLF6 (beta = 5.792 kg/m2 per-allele, 95 % confidence interval (CI): 3.885, 7.698; p = 3.43 × 10−9)—and suggestive SNPs with p < 5 × 10−6 in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta = −1.111 kg/m2, 95 % CI: −1.578, −0.645; p = 3.33 × 10−6) and WHI Hispanics (beta = −0.304 kg/m2, 95 % CI: −0.613, 0.006; p = 0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10−3) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta = 1.104 kg/m2, 95 % CI: 0.643, 1.564; p = 2.85 × 10−6) and WHI African Americans (beta = 0.219 kg/m2, 95 % CI: −0.021, 0.460; p = 0.074).ConclusionsTwo BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0387-0) contains supplementary material, which is available to authorized users.
Highlights
Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups
After systematic adjustment for the first two ethnic-specific principal components (PCs) in linear models, these λ estimates were significantly improved (λ = 1.000 for Multi-ethnic Study of Atherosclerosis (MESA) Hispanics, λ = 1.035 for Women’s Health Initiative (WHI) Hispanics, and λ = 1.034 for WHI African Americans), and all λ values were below our predetermined threshold of 1.05
By employing an ethnic-specific Genome-wide association studies (GWAS) approach, we identified suggestive body mass index (BMI)-associated single-nucleotide polymorphisms (SNPs) in Hispanics, African Americans, and European Americans that can be explored in future studies
Summary
Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. We compared findings across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women’s Health Initiative (WHI). Obesity GWAS have either analyzed a single ethnic group in isolation or pooled multiethnic data in cross-ethnic metaanalyses, assuming that genetic effects are fixed across ethnic groups, and have rarely attempted to thoroughly compare and contrast findings across ethnic groups
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