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The genetic regulatory signature of type 2 diabetes in human skeletal muscle.
Scott, Laura J; Erdos, Michael R; Huyghe, Jeroen R; Welch, Ryan P; Beck, Andrew T; Wolford, Brooke N; Chines, Peter S; Didion, John P; Narisu, Narisu; Stringham, Heather M; Taylor, D Leland; Jackson, Anne U; Vadlamudi, Swarooparani; Bonnycastle, Lori L; Kinnunen, Leena; Saramies, Jouko; Sundvall, Jouko; Albanus, Ricardo D'Oliveira; Kiseleva, Anna; Hensley, John; Crawford, Gregory E; Jiang, Hui; Wen, Xiaoquan; Watanabe, Richard M; Lakka, Timo A; Mohlke, Karen L; Laakso, Markku; Tuomilehto, Jaakko; Koistinen, Heikki A; Boehnke, Michael; Collins, Francis S; Parker, Stephen C J.
Afiliación
  • Scott LJ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Erdos MR; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Huyghe JR; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Welch RP; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Beck AT; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Wolford BN; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Chines PS; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Didion JP; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Narisu N; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Stringham HM; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Taylor DL; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Jackson AU; European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
  • Vadlamudi S; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Bonnycastle LL; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
  • Kinnunen L; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Saramies J; Department of Health, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.
  • Sundvall J; South Karelia Central Hospital, Lappeenranta 53130, Finland.
  • Albanus RD; Department of Health, National Institute for Health and Welfare, P.O. Box 30, Helsinki FI-00271, Finland.
  • Kiseleva A; Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Hensley J; Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Crawford GE; Department of Computational Medicine &Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Jiang H; Center for Genomic &Computational Biology, Duke University, Durham, North Carolina 27708, USA.
  • Wen X; Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27708, USA.
  • Watanabe RM; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Lakka TA; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • Mohlke KL; Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California 90089, USA.
  • Laakso M; Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, California 90089, USA.
  • Tuomilehto J; Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio FI-00100, Finland.
  • Koistinen HA; Kuopio Research Institute of Exercise Medicine, Kuopio FI-00100, Finland.
  • Boehnke M; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio FI-00100, Finland.
  • Collins FS; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
  • Parker SC; Department of Medicine, University of Eastern Finland, Kuopio FI-00100, Finland.
Nat Commun ; 7: 11764, 2016 06 29.
Article en En | MEDLINE | ID: mdl-27353450
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Músculo Esquelético / Diabetes Mellitus Tipo 2 / Estudio de Asociación del Genoma Completo Límite: Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Músculo Esquelético / Diabetes Mellitus Tipo 2 / Estudio de Asociación del Genoma Completo Límite: Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos