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

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, Anne U. Jackson, Swarooparani Vadlamudi, Lori L. Bonnycastle, Leena Kinnunen, Jouko Saramies, Jouko Sundvall, Ricardo D'Oliveira Albanus, Anna Kiseleva, John Hensley, Gregory E. Crawford, Hui Jiang, Xiaoquan Wen, Richard M. Watanabe, Timo A. Lakka, Karen L. Mohlke, Markku Laakso, Jaakko Tuomilehto, Heikki A. Koistinen, Michael Boehnke, Francis S. Collins () and Stephen C. J. Parker ()
Additional contact information
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
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
Hui Jiang: University of Michigan
Xiaoquan Wen: University of Michigan
Richard M. Watanabe: Keck School of Medicine of USC
Timo A. Lakka: Institute of Biomedicine/Physiology, University of Eastern Finland
Karen L. Mohlke: University of North Carolina
Markku Laakso: University of Eastern Finland
Jaakko Tuomilehto: Chronic Disease Prevention Unit, National Institute for Health and Welfare
Heikki A. Koistinen: National Institute for Health and Welfare
Michael Boehnke: University of Michigan
Francis S. Collins: National Human Genome Research Institute, National Institutes of Health
Stephen C. J. Parker: University of Michigan

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11764

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