Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

Xue, A.; Wu, Y.; Zhu, Z.; Zhang, F.; Kemper, K. E.; Zheng, Z.; Yengo, L.; Lloyd-Jones, L. R.; Sidorenko, J.; eQTLGen Consortium,; McRae, A. F.; Visscher, P. M.; Zeng, J.; Yang, J.

doi:10.1101/284570

bioRxiv · 10.1101/284570

Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes

Xue, A.·Wu, Y.·Zhu, Z.·Zhang, F.·Kemper, K. E.·Zheng, Z.·Yengo, L.·Lloyd-Jones, L. R.·Sidorenko, J.·eQTLGen Consortium,·McRae, A. F.·Visscher, P. M.·Zeng, J.·Yang, J.

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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.

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Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K. E., Zheng, Z., Yengo, L., Lloyd-Jones, L. R., Sidorenko, J., eQTLGen Consortium,, McRae, A. F., Visscher, P. M., Zeng, J., Yang, J.. 2018-03-20. Novel susceptibility loci and genetic regulation mechanisms for type 2 diabetes. https://doi.org/10.1101/284570

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