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.
- van de Bunt M Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
- Manning Fox JE Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- Dai X Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- Barrett A Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
- Grey C Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- Li L Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- Bennett AJ Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
- Johnson PR Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
- Rajotte RV Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- Gaulton KJ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
- Dermitzakis ET Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
- MacDonald PE Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- McCarthy MI Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
- Gloyn AL Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
- 2015-12-02
Published in:
- PLoS genetics. - 2015
Diabetes Mellitus, Type 2
Exons
Gene Expression Regulation
Genetic Predisposition to Disease
Genome-Wide Association Study
Glucose
Humans
Insulin
Insulin Secretion
Insulin-Secreting Cells
Quantitative Trait Loci
Signal Transduction
Transcription Factors
English
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. At 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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1371/journal.pgen.1005694
- PMID 26624892
- Persistent URL
- https://sonar.ch/global/documents/118391
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