mRNA-seq of 278 diverse skeletal muscle biopsies reveals mechanistic insights about type 2 diabetes genetic risk and identifies disease state specific eQTLs. J. R. Huyghe1, S. C. J. Parker2, M. R. Erdos2, H. Koistinen3, P. S. Chines2, R. Welch1, X. Wen1, H. Jiang1, N. Narisu2, L. Taylor2, B. Wolford2, L. J. Scott1, H. Stringham1, L. Kinnunen3, T. Blackwell1, A. U. Jackson1, Y. Lee1, A. J. Swift2, L. Bonnycastle2, M. L. Stitzel4, R. M. Watanabe5,6, K. Mohlke7, T. Lakka8, M. Laakso8, J. Tuomilehto3, F. S. Collins2, M. Boehnke1 1) Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA; 2) National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 3) National Institute for Health and Wellfare, Helsinki, Finland; 4) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; 5) Department of Preventive Medicine, University of Southern California (USC) Keck School of Medicine, Los Angeles, CA, USA; 6) Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA, USA; 7) Department of Genetics, University of North Carolina, Chapel Hill, NC, CA, USA; 8) University of Eastern Finland, Kuopio, Finland.

   Type 2 diabetes (T2D) is a complex disease caused by an interplay between genes, environment, and behavioral factors, acting over time and across multiple tissues. Genome-wide association studies (GWAS) have identified 80 loci associated with T2D risk. For most identified loci, the causal gene and functional variant(s) remain elusive because the associated region resides in noncoding DNA, suggesting a major contribution of transcriptional regulatory elements to disease risk. Regulatory element usage is often tissue-specific. Therefore, a crucial next step to guide the functional follow-up of GWAS is to determine the relationship between single nucleotide polymorphisms (SNPs) associated with T2D or related traits, and gene expression in disease-relevant tissues and across disease progression. As part of the Finland-United States Investigation of NIDDM Genetics (FUSION) study, we obtained vastus lateralis skeletal muscle biopsies from 278 clinically well-characterized Finns with normal and impaired glucose tolerance, and with newly diagnosed T2D without antihyperglycemic medication. Skeletal muscle is a major insulin target tissue and accounts for ~25-30% of postprandial glucose uptake. We performed dense genotyping, phasing, and imputation, constructed strand-specific mRNA-seq libraries, and sequenced 15.3 billion fragments (mean depth 55 million 101 base read pairs). We identified 8000 genes with expression and/or splicing quantitative trait loci (e/sQTL) (5% FDR). Some of these eQTL (e.g., for the genes TTNT3 and SDCCAG8) appear disease state specific. Multiple eQTL in our catalog are in high linkage disequilibrium with GWAS SNPs for T2D or related traits, highlighting genes at these loci as probable candidates for a role in T2D risk. Interestingly, for a subset of these GWAS SNP overlapping eQTL, gene expression is also significantly associated with T2D or a glycemic trait. E.g., T2D GWAS index SNP rs516946 is the most significant eQTL SNP for the ANK1 gene, which is differentially expressed between normal glucose tolerant vs. T2D individuals. Similarly, our eQTL analysis points out CCHCR1, associated to glycemic traits and BMI, as a candidate gene for the T2D GWAS index SNP rs3130501. This rich data resource enables identification of diverse molecular processes involved in skeletal-muscle-based insulin resistance and changes in gene transcription with progression towards T2D, and reveals mechanistic insights about T2D risk.

You may contact the first author (during and after the meeting) at