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

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Scott , L J , Erdos , M R , Huyghe , J R , Welch , R P , Beck , A T , Wolford , B N , Chines , P S , Didion , J P , Narisu , N , Stringham , H M , Taylor , D L , Jackson , A U , Vadlamudi , S , Bonnycastle , L L , Kinnunen , L , Saramies , J , Sundvall , J , Albanus , R DO , Kiseleva , A , Hensley , J , Crawford , G E , Jiang , H , Wen , X , Watanabe , R M , Lakka , T A , Mohlke , K L , Laakso , M , Tuomilehto , J , Koistinen , H A , Boehnke , M , Collins , F S & Parker , S C J 2016 , ' The genetic regulatory signature of type 2 diabetes in human skeletal muscle ' , Nature Communications , vol. 7 , 11764 .

Title: The genetic regulatory signature of type 2 diabetes in human skeletal muscle
Author: 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 Allan; Boehnke, Michael; Collins, Francis S.; Parker, Stephen C. J.
Contributor organization: Clinicum
Department of Medicine
Endokrinologian yksikkö
Date: 2016-06
Language: eng
Number of pages: 12
Belongs to series: Nature Communications
ISSN: 2041-1723
Abstract: Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the 4100 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.
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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