The trans-ancestral genomic architecture of glycemic traits

Ji Chen, Cassandra N Spracklen, Gaëlle Marenne, Arushi Varshney, Laura J Corbin, Jian'an Luan, Sara M Willems, Ying Wu, Xiaoshuai Zhang, Momoko Horikoshi, Thibaud S Boutin, Reedik Mägi, Johannes Waage, Ruifang Li-Gao, Kei Hang Katie Chan, Jie Yao, Mila D Anasanti, Audrey Y Chu, Annique Claringbould, Jani HeikkinenJaeyoung Hong, Jouke-Jan Hottenga, Shaofeng Huo, Marika A Kaakinen, Tin Louie, Winfried März, Hortensia Moreno-Macias, Anne Ndungu, Sarah C Nelson, Ilja M Nolte, Kari E North, Chelsea K Raulerson, Debashree Ray, Rebecca Rohde, Denis Rybin, Claudia Schurmann, Xueling Sim, Tarunveer S Ahluwalia, Thomas Sparsø, Arne Astrup, Marit E Jørgensen, Allan Linneberg, Betina Thuesen, Henrik Vestergaard, Hans Bisgaard, Klaus Bønnelykke, Torben Hansen, Peter Schwarz, Thorkild I A Sørensen, Nick J Wareham, LifeLines Cohort study


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.

TidsskriftNature Genetics
Udgave nummer6
Sider (fra-til)840-860
Antal sider21
StatusUdgivet - jun. 2021


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