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PLoS Genet. 2015 Dec 1;11(12):e1005694. doi: 10.1371/journal.pgen.1005694. eCollection 2015 Dec.

Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors.

Author information

1
Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
3
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
4
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
5
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
6
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
7
Department of Genetics, Stanford University, Stanford, California, United States of America.
8
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
9
Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, Geneva, Switzerland.
10
Swiss Institute of Bioinformatics, Geneva, Switzerland.
11
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.

Abstract

The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. β€ŽAt some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci.

PMID:
26624892
PMCID:
PMC4666611
DOI:
10.1371/journal.pgen.1005694
[Indexed for MEDLINE]
Free PMC Article

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