title: The genetic regulatory signature of type 2 diabetes in human skeletal muscle.
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.
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jeroen R
authors.initials: JR
authors.lastname: Huyghe
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Welch
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Beck
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Brooke N
authors.initials: BN
authors.lastname: Wolford
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Didion
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stringham
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.|European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
authors.forename: D Leland
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Swarooparani
authors.initials: S
authors.lastname: Vadlamudi
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.affiliation: Department of Health, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Kinnunen
authors.affiliation: South Karelia Central Hospital, Lappeenranta 53130, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Saramies
authors.affiliation: Department of Health, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Sundvall
authors.affiliation: Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ricardo D'Oliveira
authors.initials: RD
authors.lastname: Albanus
authors.affiliation: Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiseleva
authors.affiliation: Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hensley
authors.affiliation: Center for Genomic &Computational Biology, Duke University, Durham, North Carolina 27708, USA.|Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27708, USA.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California 90089, USA.|Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, California 90089, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.affiliation: Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio FI-00100, Finland.|Kuopio Research Institute of Exercise Medicine, Kuopio FI-00100, Finland.|Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio FI-00100, Finland.
authors.forename: Timo A
authors.initials: TA
authors.lastname: Lakka
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: Department of Medicine, University of Eastern Finland, Kuopio FI-00100, Finland.|Kuopio University Hospital, Kuopio FI-00100, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: Chronic Disease Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.|Center for Vascular Prevention, Danube University Krems, Krems 3500, Austria.|Diabetes Research Group, King Abdulaziz University, Jeddah 21589, Saudi Arabia.|Dasman Diabetes Institute, Dasman 15461, Kuwait.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.affiliation: Department of Health, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.|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.|Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki FI-00290, Finland.
authors.forename: Heikki A
authors.initials: HA
authors.lastname: Koistinen
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Stephen C J
authors.initials: SC
authors.lastname: Parker
mesh_terms: D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger; D017423:Sequence Analysis, RNA
chemical_list: D012333:RNA, Messenger