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 Magi, 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 Maerz, Hortensia Moreno-Macias, Anne Ndungu, Sarah C. Nelson, Ilja M. Nolte, Kari E. North, Emil V. R. Appel, Jun Liu, Thomas Sparso, Jing-Hua Zhao, Arne Astrup, Marit E. Jørgensen, Allan Linneberg, Henrik Vestergaard, Hans Bisgaard, Klaus Bønnelykke, Niels Grarup, Torben Hansen, Peter Kovacs, Lars Lind, Ruth J. F. Loos, Inger Njølstad, Oluf Pedersen, Peter Schwarz, Thorkild I. A. Sorensen, Meta-Analysis of Glucose and Insulin-Related Trait Consortium (MAGIC)

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Abstract

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.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind53
Udgave nummer6
Sider (fra-til)840-860
Antal sider41
ISSN1061-4036
DOI
StatusUdgivet - 2021

Bibliografisk note

CURIS 2021 NEXS 206

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