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Nat Commun. 2016 Jun 29;7:11764. doi: 10.1038/ncomms11764.

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

Author information

1
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
2
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
4
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
5
Department of Health, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.
6
South Karelia Central Hospital, Lappeenranta 53130, Finland.
7
Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
8
Center for Genomic &Computational Biology, Duke University, Durham, North Carolina 27708, USA.
9
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27708, USA.
10
Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California 90089, USA.
11
Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, California 90089, USA.
12
Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio FI-00100, Finland.
13
Kuopio Research Institute of Exercise Medicine, Kuopio FI-00100, Finland.
14
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio FI-00100, Finland.
15
Department of Medicine, University of Eastern Finland, Kuopio FI-00100, Finland.
16
Kuopio University Hospital, Kuopio FI-00100, Finland.
17
Chronic Disease Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.
18
Center for Vascular Prevention, Danube University Krems, Krems 3500, Austria.
19
Diabetes Research Group, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
20
Dasman Diabetes Institute, Dasman 15461, Kuwait.
21
Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 340, Haartmaninkatu 4, Helsinki FI-00029, Finland.
22
Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki FI-00290, Finland.
23
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

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.

PMID:
27353450
PMCID:
PMC4931250
DOI:
10.1038/ncomms11764
[Indexed for MEDLINE]
Free PMC Article

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