Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Angli Xue, Yang Wu, Zhihong Zhu, Futao Zhang, Kathryn E. Kemper, Zhili Zheng, Loic Yengo, Luke R. Lloyd-Jones, Julia Sidorenko, Yeda Wu, Allan F. McRae, Peter M. Visscher, Jian Zeng () and Jian Yang ()
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Angli Xue: The University of Queensland
Yang Wu: The University of Queensland
Zhihong Zhu: The University of Queensland
Futao Zhang: The University of Queensland
Kathryn E. Kemper: The University of Queensland
Zhili Zheng: The University of Queensland
Loic Yengo: The University of Queensland
Luke R. Lloyd-Jones: The University of Queensland
Julia Sidorenko: The University of Queensland
Yeda Wu: The University of Queensland
Allan F. McRae: The University of Queensland
Peter M. Visscher: The University of Queensland
Jian Zeng: The University of Queensland
Jian Yang: The University of Queensland

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

Date: 2018
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DOI: 10.1038/s41467-018-04951-w

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