Hara Kazuo, Fujita Hayato, Johnson Todd A, Yamauchi Toshimasa, Yasuda Kazuki, Horikoshi Momoko, Peng Chen, Hu Cheng, Ma Ronald C W, Imamura Minako, Iwata Minoru, Tsunoda Tatsuhiko, Morizono Takashi, Shojima Nobuhiro, So Wing Yee, Leung Ting Fan, Kwan Patrick, Zhang Rong, Wang Jie, Yu Weihui, Maegawa Hiroshi, Hirose Hiroshi, Kaku Kohei, Ito Chikako, Watada Hirotaka, Tanaka Yasushi, Tobe Kazuyuki, Kashiwagi Atsunori, Kawamori Ryuzo, Jia Weiping, Chan Juliana C N, Teo Yik Ying, Shyong Tai E, Kamatani Naoyuki, Kubo Michiaki, Maeda Shiro, Kadowaki Takashi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Hum Mol Genet. 2014 Jan 1;23(1):239-46. doi: 10.1093/hmg/ddt399. Epub 2013 Aug 14.
Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.
尽管已确定了60多个2型糖尿病（T2D）相关基因座，但仍有很大一部分遗传因素有待阐明。为了探索T2D的未知基因座，我们对6209637个单核苷酸多态性（SNP）进行了全基因组关联研究（GWAS），这些SNP在5976例日本T2D患者和20829例非糖尿病个体中通过直接基因分型或使用千人基因组计划（2011年6月发布）的东亚参考数据进行了推算。选择了19个未报告的基因座进行后续分析。联合发现和后续分析（30392例病例和34814例对照）确定了3个具有全基因组显著性的新基因座，分别是MIR129-LEP [rs791595；风险等位基因=A；风险等位基因频率（RAF）=0.080；P=2.55×10^(-13)；优势比（OR）=1.17]、GPSM1 [rs11787792；风险等位基因=A；RAF=0.874；P=1.74×10^(-10)；OR=1.15]和SLC16A13（rs312457；风险等位基因=G；RAF=0.078；P=7.69×10^(-13)；OR=1.20）。这项研究表明，基于使用现代参考单倍型（如千人基因组计划数据中的单倍型）推算基因型的GWAS有助于识别常见疾病的新基因座。
