Akiyama Koichi, Takeuchi Fumihiko, Isono Masato, Chakrawarthy Sureka, Nguyen Quang Ngoc, Wen Wanqing, Yamamoto Ken, Katsuya Tomohiro, Kasturiratne Anuradhani, Pham Son Thai, Zheng Wei, Matsushita Yumi, Kishimoto Miyako, Do Loi Doan, Shu Xiao-Ou, Wickremasinghe Ananda R, Kajio Hiroshi, Kato Norihiro
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
PLoS One. 2014 Jun 30;9(6):e101329. doi: 10.1371/journal.pone.0101329. eCollection 2014.
BACKGROUND/OBJECTIVE: The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts.
The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison.
We first examined the LD relationship between FTO SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target FTO region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations--Japanese, Vietnamese, Sri Lankan and Chinese (n≤26,109 for BMI association and n≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for FTO.
Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations--Europeans, Asians and Africans--are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.
背景/目的：在全基因组关联研究（GWAS）中，FTO基因第一个内含子中的16q12.2位点与体重指数（BMI）和2型糖尿病密切相关。为提高FTO基因精细定位的分辨率，我们采用了一种由两部分组成的系统方法。
第一部分是将相关变异划分为连锁不平衡（LD）簇，然后进行条件分析和单倍型分析。第二部分是通过跨种族比较筛选潜在因果变异列表。
我们首先研究了在日本GWAS中与2型糖尿病显著相关的FTO单核苷酸多态性（SNP）之间以及先前在欧洲GWAS中报道的SNP之间的LD关系。我们可以将目标FTO区域中所有显示出显著关联的检测或推算SNP划分为7个LD簇。在4个亚洲裔人群（日本人、越南人、斯里兰卡人和中国人，BMI关联研究的样本量n≤26,109，2型糖尿病关联研究的样本量n≤24,079）中检测9个选定的SNP，我们鉴定出一个由一组SNP标记的责任单倍型，并成功将潜在因果变异列表缩小至25个SNP，这是迄今为止FTO相关研究中数量最少的。
我们的数据支持，当后续研究纳入欧洲人、亚洲人和非洲人这三个距离较远的人群时，从处于强LD状态的变异中解析出因果变异的能力会持续增强。必须指出的是，这种精细定位方法的优点是可应用于现有的GWAS数据集，并结合对选定变异的直接基因分型。
