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 × 10⁻⁸), 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学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，包括多达 281,416 名无糖尿病个体（30% 非欧洲血统），这些个体的空腹血糖、口服葡萄糖激发后 2 小时血糖、糖化血红蛋白和空腹胰岛素数据均可用。跨祖先和单祖先荟萃分析确定了 242 个基因座（99 个新基因座； P < 5 × 10 ^-8 ），其中 80% 没有明显的祖先间异质性证据。仅限于具有同等样本量的欧洲血统个体的分析将导致新基因座减少 24 个。与单祖先分析相比，同等大小的跨祖先精细映射将 99% 可信集中的估计变异数量减少了中位数 37.5%。基因组特征、基因表达和基因集分析揭示了每个性状的独特生物学特征，突出了不同的潜在生物学途径。我们的结果通过使用跨祖先研究来提高功效和分辨率，增加了我们对糖尿病病理生理学的理解。