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The genetic regulatory signature of type 2 diabetes in human skeletal muscle

Author

Listed:
  • Laura J. Scott

    (University of Michigan)

  • Michael R. Erdos

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

  • Jeroen R. Huyghe

    (University of Michigan)

  • Ryan P. Welch

    (University of Michigan)

  • Andrew T. Beck

    (University of Michigan)

  • Brooke N. Wolford

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

  • Peter S. Chines

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

  • John P. Didion

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

  • Narisu Narisu

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

  • Heather M. Stringham

    (University of Michigan)

  • D. Leland Taylor

    (National Human Genome Research Institute, National Institutes of Health
    European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus)

  • Anne U. Jackson

    (University of Michigan)

  • Swarooparani Vadlamudi

    (University of North Carolina)

  • Lori L. Bonnycastle

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

  • Leena Kinnunen

    (National Institute for Health and Welfare)

  • Jouko Saramies

    (South Karelia Central Hospital)

  • Jouko Sundvall

    (National Institute for Health and Welfare)

  • Ricardo D'Oliveira Albanus

    (University of Michigan)

  • Anna Kiseleva

    (University of Michigan)

  • John Hensley

    (University of Michigan)

  • Gregory E. Crawford

    (Center for Genomic & Computational Biology, Duke University
    Duke University Medical Center)

  • Hui Jiang

    (University of Michigan)

  • Xiaoquan Wen

    (University of Michigan)

  • Richard M. Watanabe

    (Keck School of Medicine of USC
    Keck School of Medicine of USC)

  • Timo A. Lakka

    (Institute of Biomedicine/Physiology, University of Eastern Finland
    Kuopio Research Institute of Exercise Medicine
    Kuopio University Hospital, University of Eastern Finland)

  • Karen L. Mohlke

    (University of North Carolina)

  • Markku Laakso

    (University of Eastern Finland
    Kuopio University Hospital)

  • Jaakko Tuomilehto

    (Chronic Disease Prevention Unit, National Institute for Health and Welfare
    Center for Vascular Prevention, Danube University Krems
    Diabetes Research Group, King Abdulaziz University
    Dasman Diabetes Institute)

  • Heikki A. Koistinen

    (National Institute for Health and Welfare
    University of Helsinki and Helsinki University Central Hospital
    Minerva Foundation Institute for Medical Research)

  • Michael Boehnke

    (University of Michigan)

  • Francis S. Collins

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

  • Stephen C. J. Parker

    (University of Michigan
    University of Michigan)

Abstract

Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the >100 variants associated with T2D and related traits in genome-wide association studies (GWAS), >90% occur in non-coding regions, suggesting a strong regulatory component to T2D risk. Here to understand how T2D status, metabolic traits and genetic variation influence gene expression, we analyse skeletal muscle biopsies from 271 well-phenotyped Finnish participants with glucose tolerance ranging from normal to newly diagnosed T2D. We perform high-depth strand-specific mRNA-sequencing and dense genotyping. Computational integration of these data with epigenome data, including ATAC-seq on skeletal muscle, and transcriptome data across diverse tissues reveals that the tissue-specific genetic regulatory architecture of skeletal muscle is highly enriched in muscle stretch/super enhancers, including some that overlap T2D GWAS variants. In one such example, T2D risk alleles residing in a muscle stretch/super enhancer are linked to increased expression and alternative splicing of muscle-specific isoforms of ANK1.

Suggested Citation

  • Laura J. Scott & Michael R. Erdos & Jeroen R. Huyghe & Ryan P. Welch & Andrew T. Beck & Brooke N. Wolford & Peter S. Chines & John P. Didion & Narisu Narisu & Heather M. Stringham & D. Leland Taylor &, 2016. "The genetic regulatory signature of type 2 diabetes in human skeletal muscle," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11764
    DOI: 10.1038/ncomms11764
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    Cited by:

    1. Xueyan Wu & Hui Ying & Qianqian Yang & Qian Yang & Haoyu Liu & Yilan Ding & Huiling Zhao & Zhihe Chen & Ruizhi Zheng & Hong Lin & Shuangyuan Wang & Mian Li & Tiange Wang & Zhiyun Zhao & Min Xu & Yuhon, 2024. "Transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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