Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Tina Rönn

Tina Rönn

Assistant researcher

Tina Rönn

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

Author

  • Anders H Olsson
  • Petr Volkov
  • Karl Bacos
  • Tasnim Dayeh
  • Elin Hall
  • Emma A Nilsson
  • Claes Ladenvall
  • Tina Rönn
  • Charlotte Ling

Summary, in English

Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs) with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs) and 11,735 CpG sites (2.5% of tested CpGs), and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs) and 383 CpG sites (0.08% of tested CpGs), showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT) identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19) directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9%) CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and epigenetic variation interacts to influence gene expression, islet function and potential diabetes risk in humans.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Epigenetics
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2014

Language

English

Publication/Series

PLoS Genetics

Volume

10

Issue

11

Document type

Journal article

Publisher

Public Library of Science

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Epigenetics

ISBN/ISSN/Other

  • ISSN: 1553-7404