Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan.
Hum Mol Genet. 2012 Jul 1;21(13):3042-9. doi: 10.1093/hmg/dds113. Epub 2012 Mar 28.
To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.
为了鉴定 2 型糖尿病的新易感基因座，我们在日本人群中进行了基于单体型的全基因组关联研究（GWAS），该研究利用先前报道的同一样本中直接基因分型 GWAS 数据所估计的 2229890 个单核苷酸多态性（SNP）的新获得的单体型数据（第 1 阶段：4470 例 2 型糖尿病与 3071 例对照）。我们在第 1 阶段部分样本中（2692 例 2 型糖尿病与 3071 例对照）直接基因分型了 43 个 P 值<10(-4)的新 SNP，并且在另外 11139 个日本人中评估了验证 SNP 的相关性（第 2 阶段：7605 例 2 型糖尿病与 3534 例对照）。使用第 1 和第 2 阶段的直接基因分型数据进行联合荟萃分析表明，ANK1 中的 rs515071 和 MGC21675 附近的 rs7656416 在日本人群中与 2 型糖尿病具有全基因组显著水平的相关性（P < 5 × 10(-8)）。rs515071 的相关性也在欧洲 GWAS 数据中观察到（所有人群的合并 P = 6.14 × 10(-10)）。rs7656416 与 rs6815464 连锁不平衡，后者最近在东亚 2 型糖尿病 GWAS 的荟萃分析中被确定为最高信号（第 2 阶段 r(2) = 0.76）。rs7656416 与 2 型糖尿病的相关性在条件下 rs6815464 后消失。这些结果表明，ANK1 基因座是不同种族人群中 2 型糖尿病的一个新的常见易感基因座。直接基因分型数据中的关联信号较弱，因此信号的改善表明在这种特殊情况下单体型的重要性。
