Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

Angli Xue; Yang Wu; Zhihong Zhu; Futao Zhang; Kathryn E. Kemper; Zhili Zheng; Loïc Yengo; Luke R. Lloyd‐Jones; Julia Sidorenko; Yeda Wu; Mawussé D. T. Agbessi; Habibul Ahsan; Isabel Alves; Anand Kumar Andiappan; Philip Awadalla; Alexis J. Battle; Frank Beutner; Marc Jan Bonder; Dorret Irene Boomsma; Mark W. Christiansen; Annique Claringbould; Patrick Deelen; Tõnu Esko; Marie-Julie Favé; Lude Franke; Timothy M. Frayling; Sina A. Gharib; Gregory C. Gibson; Gibran Hemani; Rick Jansen

doi:10.1038/s41467-018-04951-w

GeneticsNature CommunicationsJul 23, 2018

Peer-reviewed journal article

Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

Angli Xue iD, Yang Wu iD, Zhihong Zhu iD, Futao Zhang iD, Kathryn E. Kemper iD, Zhili Zheng iD, Loïc Yengo iD, Luke R. Lloyd‐Jones iD, Julia Sidorenko iD, Yeda Wu iD, Mawussé D. T. Agbessi iD, Habibul Ahsan iD, Isabel Alves iD, Anand Kumar Andiappan iD, Philip Awadalla iD, Alexis J. Battle iD, Frank Beutner, Marc Jan Bonder iD, Dorret Irene Boomsma iD, Mark W. Christiansen, Annique Claringbould iD, Patrick Deelen iD, Tõnu Esko iD, Marie-Julie Favé iD, Lude Franke iD, , Jian Yang iD

Abstract

We conducted a meta-analysis of genome-wide association studies (GWAS) with [~]16 million genotyped/imputed genetic variants in 62,892 type 2 diabetes (T2D) cases and 596,424 controls of European ancestry. We identified 139 common and 4 rare (minor allele frequency < 0.01) variants associated with T2D, 42 of which (39 common and 3 rare variants) were independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2,765) and other T2D-relevant tissues (n = up to 385) with the GWAS results identified 33 putative functional genes for T2D, three of which were targeted by approved drugs. A further integration of DNA methylation (n = 1,980) and epigenomic annotations data highlighted three putative T2D genes (CAMK1D, TP53INP1 and ATP5G1) with plausible regulatory mechanisms whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. We further found evidence that the T2D-associated loci have been under purifying selection.

PDF DOI