Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans.
Multiethnic genome-wide association study identifies ethnic-specific associations with body mass index in Hispanics and African Americans.
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DOI：
10.1186/s12863-016-0387-0
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发表时间：
2016-06-13
期刊：
影响因子：
2.9
通讯作者：
DeWan AT
中科院分区：
文献类型：
--
作者：
Salinas YD;Wang L;DeWan AT
对肥胖的全基因组关联研究通常假设不同种族之间存在固定的遗传效应，很少尝试彻底比较和对比不同种族的研究结果。因此，我们的研究旨在确定与体重指数(BMI)的新的遗传关联，BMI是衡量肥胖的常见指标，并探索它们在多种族人口中的跨种族普适性。为此，我们对来自动脉粥样硬化多种族研究(MESA)的1,235名西班牙裔、706名亚洲人、1,549名非洲裔美国人和2,395名欧洲裔美国人的受试者进行了种族特有的全基因组关联分析。我们比较了不同种族的结果，并研究了来自妇女健康倡议(WHI)的3379名西班牙裔和6871名非洲裔美国人的单核苷酸多态(SNPs)与提示性体重指数关联p值。我们在梅萨拉美裔美国人中发现了一个全基因组显著的关联-KLF6的rs12253976(β = 每等位基因5.792公斤/平方米，95%可信区间(CI)：3.885，7.698；p = 3.43 × 10−9)-并建议在梅萨拉美裔美国人、欧洲裔美国人和非裔美国人中，SNP与p <； 5 × 10−6显示种族特异性影响体重指数。在这些提示SNP中，西班牙裔SNP rs12255372和非裔美国人SNP rs6435678在WHI中复制的证据最多。Rs12255372(在TCF7L2中)与MESA(Beta = −1.111，95%CI：−1.578，−0.645；p = 3.33 × 10−6)和WHI拉美裔(Beta = −0.304 kg/m2，95%CI：−0.613，0.006；p = 0.054)的低体重指数相关。这个TCF7L2内含子区域包含几个在MESA和MESA和WHI中具有低p值(p<；10−3)的SNP(rs7901695、rs4506565、rs4132670和rs12243326)，但只有rs12243326在我们的西班牙裔群体中与rs12255372处于强烈的连锁不平衡，这表明该区域存在独立的信号。Rs6435678(在ERBB4中)与MESA(BETA = 1.104，95%CI：0.643，1.564；p = 2.85 × 10−6)和WHI非裔美国人(BETA = 0.219 Kg/m2，95%CI：−0.021，0.460；p = 0.074)的较大体重指数相关。在西班牙裔人的TCF7L2内含子区域中存在两个BMI关联信号，其中一个被rs12255372标记。ERBB4 rs6435678是一个新的与非裔美国人体重指数相关的信号。总体而言，我们的数据表明，特定种族的关联参与了BMI的遗传决定。种族特异性对基于基因的肥胖治疗的发展具有潜在的影响。本文的在线版本(doi：10.1186/s12863-0160387-0)包含补充材料，授权用户可以使用。
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. 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). We 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). Two 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. The online version of this article (doi:10.1186/s12863-016-0387-0) contains supplementary material, which is available to authorized users.