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Genetics/Genomes/Proteomics/Metabolomics

Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants

  1. Soren K. Thomsen1,
  2. Alessandro Ceroni2,
  3. Martijn van de Bunt1,3,
  4. Carla Burrows1,
  5. Amy Barrett1,
  6. Raphael Scharfmann4,
  7. Daniel Ebner2,
  8. Mark I. McCarthy1,3,5 and
  9. Anna L. Gloyn1,3,5⇑
  1. 1Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
  2. 2Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
  3. 3Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, U.K.
  4. 4INSERM U1016, Institut Cochin, Université Paris Descartes, Paris, France
  5. 5National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  1. Corresponding author: Anna L. Gloyn, anna.gloyn{at}drl.ox.ac.uk.
Diabetes 2016 Dec; 65(12): 3805-3811. https://doi.org/10.2337/db16-0361
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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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0361/-/DC1.

  • See accompanying article, p. 3541.

  • Received March 17, 2016.
  • Accepted August 18, 2016.
  • © 2016 by the American Diabetes Association.
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Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants
Soren K. Thomsen, Alessandro Ceroni, Martijn van de Bunt, Carla Burrows, Amy Barrett, Raphael Scharfmann, Daniel Ebner, Mark I. McCarthy, Anna L. Gloyn
Diabetes Dec 2016, 65 (12) 3805-3811; DOI: 10.2337/db16-0361

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Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants
Soren K. Thomsen, Alessandro Ceroni, Martijn van de Bunt, Carla Burrows, Amy Barrett, Raphael Scharfmann, Daniel Ebner, Mark I. McCarthy, Anna L. Gloyn
Diabetes Dec 2016, 65 (12) 3805-3811; DOI: 10.2337/db16-0361
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