The trans-ancestral genomic architecture of glycemic traits.
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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.
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1546-1718
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MRC (MC_UU_00006/1)
Medical Research Council (G0801566)
Medical Research Council (G0901213)
Medical Research Council (MR/K013491/1)
Medical Research Council (MR/N003284/1)
Wellcome Trust (107743/Z/15/Z)
MRC (MC_UU_00006/2)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
TCC (None)
Medical Research Council (G0801566/1)
Medical Research Council (G0901213/1)
Medical Research Council (G0401527/1)