Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci
Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci
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DOI：
10.1007/s00439-017-1787-6
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发表时间：
2017-06-01
期刊：
影响因子：
5.3
通讯作者：
North, Kari E.
中科院分区：
文献类型：
--
作者：
Fernandez-Rhodes, Lindsay;Gong, Jian;North, Kari E.
大多数身体质量指数（BMI）基因位点已经在主要欧洲祖先的研究中被确定。这些基因座对其他种族/民族群体的影响尚不清楚。因此，我们旨在通过基因组学和流行病学研究，对170个已建立的BMI变异或其代理在不同美国人群中的普遍性进行表征，并利用来自人口结构的bb102,000名非洲人、西班牙裔/拉丁裔、亚洲人、欧洲人和美洲印第安人/阿拉斯加原住民后裔的样本，对36个BMI位点进行跨种族精细绘制。我们在MetaboChip （Illumina, Inc.）上对BMI位点的加性单核苷酸多态性（snp）进行了BMI自然对数（18.5-70 kg/m(2)）的线性回归，调整了年龄、性别、人群分层、研究地点或亲缘关系。然后，我们进行固定效应荟萃分析和贝叶斯跨种族荟萃分析，通过等位基因频率差异进行经验聚类。最后，我们近似条件关联和联合关联，以测试二次信号的存在。我们注意到与先前报告的风险等位基因的方向性一致性超出了预期的偶然性（二项p < 0.05）。近四分之一的先前描述的BMI指数snp和代谢芯片上36个密集基因型BMI位点中的29个在跨种族分析中被复制/推广。我们在9个位点上观察到多重信号，包括描述了7个具有新颖多重信号的位点。本研究支持将最常见的遗传位点推广到不同的祖先群体，并强调了密集的多种族基因组数据在细化感兴趣的遗传位点的功能变异和描述具有多种潜在遗传变异的几个位点方面的重要性。
Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of > 102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.