The trans-ancestral genomic architecture of glycemic traits

Lifelines Cohort Study, Metaanal Glucose Insulin Related, Ji Chen, Cassandra N. Spracklen, Gaelle Marenne, Arushi Varshney, Laura J. Corbin, Jian'an Luan, Sara M. Willems, Ying Wu, Xiaoshuai Zhang, Momoko Horikoshi, Thibaud S. Boutin, Reedik Magi, Johannes Waage, Ruifang Li-Gao, Kei Hang Katie Chan, Jie Yao, Mila D. Anasanti, Audrey Y. ChuAnnique Claringbould, Jani Heikkinen, Jaeyoung Hong, Jouke-Jan Hottenga, Shaofeng Huo, Marika A. Kaakinen, Tin Louie, Winfried Maerz, Hortensia Moreno-Macias, Anne Ndungu, Sarah C. Nelson, Ilja M. Nolte, Kari E. North, Ayse Demirkan, Young Jin Kim, Serena Sanna, Albert V. Smith, Peter J. van der Most, Niek Verweij, Tian Xie, Jing-Hua Zhao, Wei Zhao, Stephan J. L. Bakker, Catharina A. Hartman, Dennis Raven, Jana V. van Vliet-Ostaptchouk, D. I. Boomsma, Wei Huang, Meena Kumari, Harold Snieder, Pim van der Harst, Ya X. Wang, Albertine J. Oldehinkel

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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 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.

Original languageEnglish
Pages (from-to)840-860
Number of pages41
JournalNature Genetics
Early online date31-May-2021
Publication statusPublished - Jun-2021


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