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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
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,Crdoi
10.1038/ncomms11764subject
Has Abstractpub_date
2016-06-29 00:00:00pages
11764issn
2041-1723pii
ncomms11764journal_volume
7pub_type
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