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Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Nat Genet. 2022 May;54(5):560-572. doi: 10.1038/s41588-022-01058-3. Epub 2022 May 12.
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
我们通过跨种族关联研究糖尿病荟萃分析（DIAMANTE）联盟，在180,834名2型糖尿病（T2D）患者和1,159,055名对照者（48.9%为非欧洲血统）中，汇集了一组具有广泛祖先多样性的全基因组关联研究（GWAS）。多祖先GWAS荟萃分析确定了237个达到严格全基因组显著性水平（P < 5 × 10）的基因座，这些基因座被划分为338个不同的关联信号。多祖先荟萃分析样本量的增加和群体多样性的扩大，增强了对这些信号的精细定位，将54.4%的T2D关联定位到后验概率>50%的单个变异上。这种改进的精细定位能够系统地评估介导T2D关联的候选因果基因和分子机制，为功能研究奠定了基础。多祖先遗传风险评分提高了T2D预测在不同人群中的可转移性。我们的研究朝着更有效地将T2D的GWAS临床转化迈出了一步，以改善所有人的全球健康，无论其遗传背景如何。
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