Federal Research Center Institute of Cytology and Genetics SB RAS, 10 Lavrentieva Ave, Novosibirsk, Russian Federation, 630090.
Novosibirsk State University, 2 Pirogova Str, Novosibirsk, Russian Federation, 630090.
BMC Med Genomics. 2019 Mar 13;12(Suppl 2):46. doi: 10.1186/s12920-019-0491-x.
Fat mass and obesity-associated (FTO) gene has been under close investigation since the discovery of its high impact on the obesity status in 2007 by a range of publications. Recent report on its implication in adipocytes underscored its molecular and functional mechanics in pathology. Still, the population specific features of the locus structure have not been approached in detail.
We analyzed the population specific haplotype profiles of FTO genomic locus identified by Genome Wide Association Studies (GWAS) for the high obesity risk by examining eighteen 1000G populations from 4 continental groups. The GWAS SNPs cluster is located in the FTO gene intron 1 spanning around 70 kb.
We reconstructed the ancestral state of the locus, which comprised low-risk major allele found in all populations, and two minor risk-associated alleles, each one specific for African and European populations, correspondingly. The locus structure and its allele frequency distribution underscore the high risk allele frequency specifically for the European population. South Asian populations have the second highest frequency of risk alleles, while East Asian populations have the lowest. African population-specific minor allele was only partially risk-associated. All of the GWAS SNPs considered are manifested by low risk alleles as reference (major) ones (p > 0.5) in each of the continental groups. Strikingly, rs1421085, recently reported as a causal SNP, was found to be monomorphic in ancestral (African) populations, implying possible selection sweep in the course of its rapid fixation, as reported previously.
The observations underscore varying FTO -linked risk in the manifestation of population specific epidemiology of genetically bound obesity. The results imply that the FTO locus is one of the major genetic determinants for obesity risk from GWAS SNPs set.
自 2007 年一系列出版物发现 FTO 基因（肥胖相关脂肪量和肥胖基因）对肥胖状况有重大影响以来，该基因一直受到密切关注。最近关于其在脂肪细胞中的作用的报告强调了其在病理学中的分子和功能机制。然而，该基因座的结构在特定人群中的特征尚未详细研究。
我们通过检查来自 4 个大陆组的 18 个 1000G 人群，分析了通过全基因组关联研究（GWAS）确定的 FTO 基因组基因座的特定人群单体型图谱，这些人群具有高肥胖风险。GWAS SNPs 簇位于 FTO 基因内含子 1 中，跨度约 70kb。
我们重建了该基因座的祖先状态，该状态包括所有人群中发现的低风险主要等位基因，以及两个分别与非洲和欧洲人群相关的较小风险等位基因。该基因座的结构及其等位基因频率分布强调了欧洲人群中高风险等位基因频率的特异性。南亚人群的风险等位基因频率次之，东亚人群的风险等位基因频率最低。非洲人群特有的较小等位基因仅部分与风险相关。在所考虑的所有 GWAS SNPs 中，作为参考（主要）等位基因的低风险等位基因在每个大陆组中均表现出来（p>0.5）。引人注目的是，最近报道的因果 SNP rs1421085 在祖先（非洲）人群中表现为单态性，这表明在其快速固定过程中可能发生了选择扫荡，正如之前报道的那样。
这些观察结果强调了 FTO 相关风险在表现特定人群遗传肥胖症的流行病学中的差异。结果表明，FTO 基因座是 GWAS SNPs 集中肥胖风险的主要遗传决定因素之一。
