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Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

By Angli Xue, Yang Wu, Zhihong Zhu, Futao Zhang, Kathryn E Kemper, Zhili Zheng, Loic Yengo, Luke R. Lloyd-Jones, Julia Sidorenko, Yeda Wu, eQTLGen Consortium, Allan F McRae, Peter M Visscher, Jian Zeng, Jian Yang

Posted 20 Mar 2018
bioRxiv DOI: 10.1101/284570 (published DOI: 10.1038/s41467-018-04951-w)

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.

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