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首页> 美国卫生研究院文献>PLoS Genetics >Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium
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Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

机译：在非洲血统的个体中使用全基因组关联研究的高密度插值发现和精确定位肥胖基因座：非洲祖先人体测量学遗传学联盟

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Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
机译：全基因组关联研究（GWAS）已确定与肥胖测量相关的300多个基因座，包括体重指数（BMI）和腰臀比（针对BMI，WHRadjBMI进行了调整），但通过对非洲人的筛查并未发现祖先基因组。我们使用1000个基因组第一阶段估算的GWAS，对来自非洲祖先人类遗传学遗传学联盟（AAAGC）的多达52,895个人的BMI和多达23,095个人的WHRadjBMI进行了大规模的荟萃分析和复制，以改善常见和低频变异的覆盖率在低连锁不平衡非洲血统的基因组中。在性别组合分析中，我们在WHRadjBMI中确定了一个新基因座（TCF7L2 / HABP2），在P <5×10 -8 处确定了八个先前建立的基因座：在非洲，BMI为七个，在WHRadjBMI中为一个祖先个体。当与欧洲GWAS结合使用时，为WHRadjBMI确定了另一个新基因座（SPRYD7 / DLEU2）。在按性别分层的分析中，我们在非洲个体中发现了三个新的BMI基因位点（男性为INTS10 / LPL和MLC1，女性为IRX4 / IRX2）和四个WHRadjBMI（女性为SSX2IP，CASC8，PDE3B和ZDHHC1 / HSD11B2）。祖先或非洲和欧洲祖先。对于四个新的变体，次要等位基因频率较低（<5％）。在跨族裔精细映射中，来自非洲血统的性别组合和性别分层分析的47个BMI基因座和27个WHRadjBMI基因座在整个基因座范围内具有显着意义（P <0.05，已针对每个基因座的有效变异数进行了调整），其中26个BMI基因座和17个WHRadjBMI基因座在可信集中包含≤20个变体，共同构成驱动该关联的后验概率为99％。这些基因座中的13个中的前导变体极有可能是因果关系。与我们之前由HapMap估算的BMI和WHRadjBMI的GWAS分别包括多达71,412和27,350个非洲血统的个体相比，我们的结果表明，在鉴定GWAS基因座（包括低频变体）方面，有1000个基因组推算显示出适度的提高。跨种族的荟萃分析进一步改善了非洲和欧洲血统人群之间共有的基因座中推定的因果变异的精细定位。

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