engleski

The trans-ancestral genomic architecture of glycemic traits

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 x 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. A trans- ancestry meta-analysis of GWAS of glycemic traits in up to 281, 416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine- mapping of credible variant sets.

WIDE ASSOCIATION ; INSULIN-RESISTANCE ; GENE-EXPRESSION ; DISEASE RISK ; VARIANTS ; GLUCOSE ; LOCI ; METAANALYSIS ; MECHANISMS ; HEMOGLOBIN

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