The genetic regulatory signature of type 2 diabetes in human skeletal muscle.
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.
Scott, LJ; Erdos, MR; Huyghe, JR; Welch, RP; Beck, AT; Wolford, BN; Chines, PS; Didion, JP; Narisu, N; Stringham, HM; Taylor, DL; Jackson, AU; Vadlamudi, S; Bonnycastle, LL; Kinnunen, L; Saramies, J; Sundvall, J; Albanus, RD; Kiseleva, A; Hensley, J; Crawford, GE; Jiang, H; Wen, X; Watanabe, RM; Lakka, TA; Mohlke, KL; Laakso, M; Tuomilehto, J; Koistinen, HA; Boehnke, M; Collins, FS; Parker, SCJ
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