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Title

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

Authors
van de Bunt, Martijn
Manning Fox, Jocelyn E
Dai, Xiaoqing
Barrett, Amy
Grey, Caleb
Li, Lei
Bennett, Amanda J
Johnson, Paul R
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Published in PLOS Genetics. 2015, vol. 11, no. 12, p. e1005694
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. ‎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.
Keywords Diabetes Mellitus, Type 2/genetics/pathologyExonsGene Expression RegulationGenetic Predisposition to DiseaseGenome-Wide Association StudyGlucose/metabolismHumansInsulin/genetics/secretionInsulin-Secreting Cells/metabolism/pathologyQuantitative Trait Loci/geneticsSignal TransductionTranscription Factors/biosynthesis/genetics
Identifiers
PMID: 26624892
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Article (Published version) (2.6 MB) - public document Free access
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Research group Population Genomics and Genetics of Complex Traits (892)
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VAN DE BUNT, Martijn et al. 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. In: PLOS Genetics, 2015, vol. 11, n° 12, p. e1005694. https://archive-ouverte.unige.ch/unige:89650

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Deposited on : 2016-11-30

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