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

• Published in: Nature communications Vol. 7; no. 1; pp. 11764 - 12
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.06.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 38/22; 38/39; 38/77; 38/91; 631/208/2489/144; 631/443/319/1642/137/773; 692/308; 692/4023/1671/1668/1973; Alleles; Bioinformatics; Biology; Biopsy; Body mass index; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Epigenomics; Female; Gene expression; Gene Expression Regulation; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Genomes; Glucose; Hospitals; Humanities and Social Sciences; Humans; Insulin resistance; Male; multidisciplinary; Muscle, Skeletal - metabolism; Musculoskeletal system; Physiology; Polymorphism, Single Nucleotide; Preventive medicine; RNA, Messenger; Science; Science (multidisciplinary); Sequence Analysis, RNA; North Carolina; Los Angeles California; United States > US; Finland; California; Ann Arbor Michigan; Michigan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11764

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 . More than 90% of genetic variants associated with type 2 diabetes occur in non-coding regions. Scott et al . report genomes, epigenomes and transcriptomes of skeletal muscle from 271 participants with a range of glucose tolerances, revealing a genetic regulatory architecture enriched in muscle stretch/super enhancers.