title: Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.
abstract: Most genetic association signals for type 2 diabetes risk are located in noncoding regions of the genome, hindering translation into molecular mechanisms. Physiological studies have shown a majority of disease-associated variants to exert their effects through pancreatic islet dysfunction. Systematically characterizing the role of regional transcripts in β-cell function could identify the underlying disease-causing genes, but large-scale studies in human cellular models have previously been impractical. We developed a robust and scalable strategy based on arrayed gene silencing in the human β-cell line EndoC-βH1. In a screen of 300 positional candidates selected from 75 type 2 diabetes regions, each gene was assayed for effects on multiple disease-relevant phenotypes, including insulin secretion and cellular proliferation. We identified a total of 45 genes involved in β-cell function, pointing to possible causal mechanisms at 37 disease-associated loci. The results showed a strong enrichment for genes implicated in monogenic diabetes. Selected effects were validated in a follow-up study, including several genes (ARL15, ZMIZ1, and THADA) with previously unknown or poorly described roles in β-cell biology. We have demonstrated the feasibility of systematic functional screening in a human β-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
authors.forename: Soren K
authors.identifier: http://orcid.org/0000-0001-8894-2868
authors.initials: SK
authors.lastname: Thomsen
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ceroni
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, U.K.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
authors.forename: Carla
authors.initials: C
authors.lastname: Burrows
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.affiliation: INSERM U1016, Institut Cochin, Université Paris Descartes, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ebner
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, U.K.|National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K. anna.gloyn@drl.ox.ac.uk.|Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, U.K.|National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D007328:Insulin; D009363:Neoplasm Proteins; D050828:Protein Inhibitors of Activated STAT; C477698:THADA protein, human; C507928:ZMIZ2 protein, human; D020727:ADP-Ribosylation Factors; C585870:ARL15 protein, human