TY - JOUR
T1 - The genetic regulatory signature of type 2 diabetes in human skeletal muscle
AU - Scott, Laura J.
AU - Erdos, Michael R.
AU - Huyghe, Jeroen R.
AU - Welch, Ryan P.
AU - Beck, Andrew T.
AU - Wolford, Brooke N.
AU - Chines, Peter S.
AU - Didion, John P.
AU - Narisu, Narisu
AU - Stringham, Heather M.
AU - Taylor, D. Leland
AU - Jackson, Anne U.
AU - Vadlamudi, Swarooparani
AU - Bonnycastle, Lori L.
AU - Kinnunen, Leena
AU - Saramies, Jouko
AU - Sundvall, Jouko
AU - Albanus, Ricardo D.Oliveira
AU - Kiseleva, Anna
AU - Hensley, John
AU - Crawford, Gregory E.
AU - Jiang, Hui
AU - Wen, Xiaoquan
AU - Watanabe, Richard M.
AU - Lakka, Timo A.
AU - Mohlke, Karen L.
AU - Laakso, Markku
AU - Tuomilehto, Jaakko
AU - Koistinen, Heikki A.
AU - Boehnke, Michael
AU - Collins, Francis S.
AU - Parker, Stephen C.J.
PY - 2016/6/29
Y1 - 2016/6/29
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84976612077
U2 - 10.1038/ncomms11764
DO - 10.1038/ncomms11764
M3 - Article
C2 - 27353450
AN - SCOPUS:84976612077
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 11764
ER -