Exeter Centre of Excellence for Diabetes Research (EXCEED), Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
Nat Genet. 2021 Jun;53(6):840-860. doi: 10.1038/s41588-021-00852-9. Epub 2021 May 31.
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
血糖特征用于诊断和监测 2 型糖尿病和心脏代谢健康。迄今为止，大多数血糖特征的遗传研究都集中在欧洲血统的个体上。在这里，我们汇总了全基因组关联研究，其中包括多达 281416 名无糖尿病（30%非欧洲血统）的个体，他们的空腹血糖、口服葡萄糖耐量试验后 2 小时血糖、糖化血红蛋白和空腹胰岛素数据可用。跨血统和单血统荟萃分析确定了 242 个位点（99 个新的；P<5×10），其中 80%没有明显的血统间异质性证据。将分析仅限于具有等效样本量的欧洲血统个体，将导致 24 个新的位点减少。与单血统分析相比，同等大小的跨血统精细映射将 99%可信区间中估计的变异数量中位数减少了 37.5%。基因组特征、基因表达和基因集分析为每个特征揭示了独特的生物学特征，突出了不同的潜在生物学途径。我们的研究结果通过使用跨血统研究提高了效力和分辨率，增加了我们对糖尿病病理生理学的理解。
