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

被引：132

作者：

van de Bunt, Martijn ^{[1
,2
]}

Fox, Jocelyn E. Manning ^{[3
,4
]}

Dai, Xiaoqing ^{[3
,4
]}

Barrett, Amy ^{[1
]}

Grey, Caleb ^{[3
,4
]}

Li, Lei ^{[3
,4
]}

Bennett, Amanda J. ^{[1
]}

Johnson, Paul R. ^{[1
,5
]}

Rajotte, Raymond V. ^{[3
,6
]}

Gaulton, Kyle J. ^{[2
,7
]}

Dermitzakis, Emmanouil T. ^{[8
,9
,10
]}

MacDonald, Patrick E. ^{[3
,4
]}

McCarthy, Mark I. ^{[1
,2
,11
]}

Gloyn, Anna L. ^{[1
,2
,11
]}

机构：

[1] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Alberta, Alberta Diabet Inst, Edmonton, AB, Canada

[4] Univ Alberta, Dept Pharmacol, Edmonton, AB, Canada

[5] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England

[6] Univ Alberta, Dept Surg, Edmonton, AB, Canada

[7] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[8] Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland

[9] Univ Geneva, Inst Genet & Genom Geneva iG3, Geneva, Switzerland

[10] Swiss Inst Bioinformat, Geneva, Switzerland

[11] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

来源：

PLOS GENETICS | 2015年 / 11卷 / 12期

基金：

英国医学研究理事会; 美国国家卫生研究院; 加拿大健康研究院;

关键词：

GENETIC ARCHITECTURE; INSULIN-SECRETION; PROTEIN HZIMP10; GLUCOSE; VARIANTS; LOCI; CELL; MECHANISMS; RECEPTOR; PROVIDES;

D O I：

10.1371/journal.pgen.1005694

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：21

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