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Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

Author

Listed:
  • Ana Viñuela

    (University of Geneva Medical School
    Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva
    Swiss Institute of Bioinformatics
    Newcastle University)

  • Arushi Varshney

    (University of Michigan)

  • Martijn Bunt

    (University of Oxford
    University of Oxford
    Oxford University Hospitals Trust)

  • Rashmi B. Prasad

    (Lund University, Skåne University Hospital)

  • Olof Asplund

    (Lund University, Skåne University Hospital)

  • Amanda Bennett

    (University of Oxford)

  • Michael Boehnke

    (University of Michigan)

  • Andrew A. Brown

    (University of Geneva Medical School
    Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva
    Swiss Institute of Bioinformatics
    University of Dundee, Dundee)

  • Michael R. Erdos

    (National Human Genome Research Institute, National Institutes of Health)

  • João Fadista

    (Lund University, Skåne University Hospital
    Statens Serum Institut
    University of Helsinki)

  • Ola Hansson

    (Lund University, Skåne University Hospital
    University of Helsinki)

  • Gad Hatem

    (Lund University, Skåne University Hospital)

  • Cédric Howald

    (University of Geneva Medical School
    Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva
    Swiss Institute of Bioinformatics)

  • Apoorva K. Iyengar

    (University of North Carolina)

  • Paul Johnson

    (University of Oxford)

  • Ulrika Krus

    (Lund University, Skåne University Hospital)

  • Patrick E. MacDonald

    (University of Alberta)

  • Anubha Mahajan

    (University of Oxford
    Human Genetics, Genentech)

  • Jocelyn E. Manning Fox

    (University of Alberta)

  • Narisu Narisu

    (National Human Genome Research Institute, National Institutes of Health)

  • Vibe Nylander

    (University of Oxford)

  • Peter Orchard

    (Department of Computational Medicine & Bioinformatics, University of Michigan)

  • Nikolay Oskolkov

    (Lund University, Skåne University Hospital)

  • Nikolaos I. Panousis

    (University of Geneva Medical School
    Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva
    Swiss Institute of Bioinformatics)

  • Anthony Payne

    (University of Oxford)

  • Michael L. Stitzel

    (The Jackson Laboratory for Genomic Medicine
    University of Connecticut)

  • Swarooparani Vadlamudi

    (University of North Carolina)

  • Ryan Welch

    (University of Michigan)

  • Francis S. Collins

    (National Human Genome Research Institute, National Institutes of Health)

  • Karen L. Mohlke

    (University of North Carolina)

  • Anna L. Gloyn

    (University of Oxford
    University of Oxford
    Oxford University Hospitals Trust
    Stanford University)

  • Laura J. Scott

    (University of Michigan)

  • Emmanouil T. Dermitzakis

    (University of Geneva Medical School
    Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva
    Swiss Institute of Bioinformatics)

  • Leif Groop

    (Lund University, Skåne University Hospital
    University of Helsinki)

  • Stephen C. J. Parker

    (University of Michigan
    Department of Computational Medicine & Bioinformatics, University of Michigan)

  • Mark I. McCarthy

    (University of Oxford
    University of Oxford
    Oxford University Hospitals Trust
    Human Genetics, Genentech)

Abstract

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.

Suggested Citation

  • Ana Viñuela & Arushi Varshney & Martijn Bunt & Rashmi B. Prasad & Olof Asplund & Amanda Bennett & Michael Boehnke & Andrew A. Brown & Michael R. Erdos & João Fadista & Ola Hansson & Gad Hatem & Cédric, 2020. "Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18581-8
    DOI: 10.1038/s41467-020-18581-8
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