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.
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.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Dai
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Caleb
authors.initials: C
authors.lastname: Grey
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bennett
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Johnson
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Raymond V
authors.initials: RV
authors.lastname: Rajotte
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Gaulton
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.|Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, Geneva, Switzerland.|Swiss Institute of Bioinformatics, Geneva, Switzerland.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D007328:Insulin; D014157:Transcription Factors; C480599:ZMIZ1 protein, human; D005947:Glucose