Genetic and epigenetic signatures of gene regulation specific to type 2 diabetes-relevant tissues

Authors

• JP Didion
• SCJ Parker
• BN Wolford
• JR Huyghe
• R Welch
• MR Erdos
• PS Chines
• N Narisu
• LJ Scott
• ML Stitzel
• M Boehnke
• FS Collins

Abstract

Multiple tissues are involved in glucose metabolism and the etiology of type 2 diabetes (T2D), including skeletal muscle, adipose, and pancreatic islets. Although hundreds of genetic variants have been associated with T2D and related traits, the tissue-specific effects of those variants are not well understood. To identify gene expression signatures in T2D-relevant tissues, we obtained muscle and adipose biopsies from 278 Finnish individuals, and pancreatic islets from 78 unrelated cadaveric donors. We performed dense genotyping and deep mRNA sequencing on all samples; whole-methylome sequencing of a subset of samples is in progress. In addition, we obtained genotype, RNA-seq and methylation data for T2D relevant tissues (including brain, liver, stomach, small intestine) from published studies. We process samples using a pipeline for imputation, transcript assembly, differential expression (including allele-specific expression) and splicing. We identify genetic elements that are enriched in each tissue, including hundreds of novel transcripts. We also identify tissue-specific expression and splicing quantitative trait loci (e/sQTL), and we use reference chromatin state maps to quantify those that occur in tissue-specific chromatin states. We have already found significant enrichment of SNPs associated with T2D in enhancer regions of muscle and islets. In addition, we will identify sites of differential methylation that are associated with e/sQTLs in a tissue-specific manner (mQTLs), which will suggest specific links between genetic and epigenetic variation in gene regulation. This resource will form the basis for further understanding the role of functional and regulatory variation in the contribution of each tissue to the etiology of T2D.

Scientific Focus Area: Genetics and Genomics

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