Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Hum Mol Genet. 2010 Jul 15;19(14):2907-16. doi: 10.1093/hmg/ddq178. Epub 2010 Apr 29.
Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 x 10(-6) and 3.61 x 10(-6) in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.
全基因组关联研究已经确定了许多与多基因性状相关的常见遗传变异，这些研究通常是在具有近期欧洲血统的个体中进行的。在这些人群中，许多常见的变异是紧密相关的，与功能性或真实变异的完美或近乎完美的替代物显示出相当的关联证据，极大地限制了精细映射的分辨率。具有近期非洲血统的人群通常具有较少的扩展和/或不同的连锁不平衡（LD）模式，并且已经被提议用于精细映射研究。在这里，我们强烈复制并在主要是非洲血统的人群中精细映射了 FTO 基因座的变异与体重指数（BMI）之间的关联，这在欧洲血统的人群中已经得到了很好的证实。我们对单核苷酸多态性进行了基因分型，这些多态性与欧洲血统个体的关联信号相关，但在非洲血统个体中具有不同程度的相关性。大多数变体，包括一个以前被认为具有功能重要性的变体，与 BMI 没有显著关联，但两个变体 rs3751812 和 rs9941349 显示出强烈的关联证据（9881 名个体的荟萃分析中分别为 P = 2.58 x 10(-6) 和 3.61 x 10(-6)）。因此，我们不仅在非洲裔人群中强烈复制了这种关联，而且还将潜在因果变异的列表缩小到与非洲人群中 rs3751812 和 rs9941349 相关的变异。这项研究说明了利用具有不同 LD 模式的人群来精细映射关联的潜力，并为在 FTO 基因座进行遗传指导的功能研究铺平了道路。
