Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets

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Inter-individual variation in genetics and epigenetics affects biological processes and disease susceptibility. However, most studies have investigated genetic and epigenetic mechanisms independently and to uncover novel mechanisms affecting disease susceptibility there is a highlighted need to study interactions between these factors on a genome-wide scale. To identify novel loci affecting islet function and potentially diabetes, we performed the first genome-wide methylation quantitative trait locus (mQTL) analysis in human pancreatic islets including DNA methylation of 468,787 CpG sites located throughout the genome. Our results showed that DNA methylation of 11,735 CpGs in 4,504 unique genes is regulated by genetic factors located in cis (67,438 SNP-CpG pairs). Furthermore, significant mQTLs cover previously reported diabetes loci including KCNJ11, INS, HLA, PDX1 and GRB10. We also found mQTLs associated with gene expression and insulin secretion in human islets. By performing causality inference tests (CIT), we identified CpGs where DNA methylation potentially mediates the genetic impact on gene expression and insulin secretion. Our functional follow-up experiments further demonstrated that identified mQTLs/genes (GPX7, GSTT1 and SNX19) directly affect pancreatic β-cell function. Together, our study provides a detailed map of genome-wide associations between genetic and epigenetic variation, which affect gene expression and insulin secretion in human pancreatic islets.

Vyšlo v časopise: Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets. PLoS Genet 10(11): e32767. doi:10.1371/journal.pgen.1004735
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004735

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