BACKGROUND SNPs in the first intron of the fat mass and obesity-associated (FTO) gene represent the strongest genome-wide associations with adiposity [body mass index (BMI)]; the molecular basis for these associations is under intense investigation. In European populations, the focus of most genome-wide association studies conducted to date, the single nucleotide polymorphisms (SNPs) have indistinguishable associations due to the high level of linkage disequilibrium (LD). However, in African American (AA) individuals, reduced LD and increased haplotype diversity permit finer distinctions among obesity-associated SNPs. Such distinctions are important to mechanistic inferences and for selection of disease SNPs relevant to specific populations. METHODS To identify specific FTO SNP(s) directly related to adiposity, we performed: 1) haplotype analyses of individual-level data in 3,335 AAs from the Atherosclerosis Risk in Communities Cohort (ARIC) study; as well as 2) statistical fine-mapping using summary statistics from a study of FTO in over 20 000 AAs and over 1000 functional genomic annotations. RESULTS Our haplotype analyses suggest that in AAs at least two distinct signals underlie the intron 1 FTO-adiposity signal. Fine mapping showed that two SNPs have the highest posterior probability of association (PPA) with BMI: rs9927317 (PPA = 0.94) and rs62033405 (PPA = 0.99). These variants overlap possible enhancer sites and the 5'-regions of transcribed genes in the substantia nigra, chondrocytes, and white adipocytes. CONCLUSIONS We found two SNPs in FTO with the highest probability of direct association with BMI in AAs, as well as tissue-specific mechanisms by which these variants may contribute to the pathogenesis of obesity.

中文翻译：

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非洲裔美国人FTO基因座的功能基因组表征。

背景技术脂肪质量和肥胖相关（FTO）基因的第一个内含子中的SNP代表与肥胖相关的最强的全基因组关联[体重指数（BMI）]；这些关联的分子基础正在深入研究。在欧洲人群中，迄今为止进行的大多数全基因组关联研究的重点是，由于高水平的连锁不平衡（LD），单核苷酸多态性（SNP）具有难以区分的关联。但是，在非洲裔美国人（AA）中，LD的降低和单倍型多样性的增加使得与肥胖相关的SNP之间存在更好的区别。此类区别对于机制推断以及与特定人群相关的疾病SNP的选择非常重要。方法为了确定与肥胖症直接相关的特定FTO SNP，我们进行了以下操作：1）通过社区队列中的动脉粥样硬化风险研究对3,335个AA中的个人数据进行单倍型分析；以及2）使用FTO在2万多个AA和100​​0多个功能基因组注释中进行的汇总统计数据进行统计精细映射。结果我们的单倍型分析表明，在AA中，内含子1 FTO肥胖信号至少有两个不同的信号。精细定位显示，两个SNP与BMI的关联度最高（rsa）：rs9927317（PPA = 0.94）和rs62033405（PPA = 0.99）。这些变体重叠了黑质，软骨细胞和白色脂肪细胞中可能的增强子位点和转录基因的5'-区域。结论我们在FTO中发现了两个SNP，它们在AA中与BMI直接关联的可能性最高，