The epigenetic regulatory architecture of type 2 diabetes: progressing from associations to mechanisms

Authors

• JP Didion
• DL Taylor
• MR Erdos
• PS Chines
• M Boehnke
• FS Collins

Abstract

Type 2 diabetes (T2D) is a metabolic disorder that results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the >100 variants significantly associated with T2D and related traits through genome-wide association studies (GWAS), 90% lie in non-coding regions of the genome, suggesting a strong regulatory component to disease susceptibility. DNA methylation may provide a causal link between genetic variation and gene expression, yet little is known about the methylation landscape in T2D-relevant tissues. I will analyze methylation in 331 matched skeletal muscle and adipose biopsies from well-phenotyped patients spanning a range of glucose tolerance categories, and ~130 cadaveric pancreatic islet samples, integrate these data with other genetic and epigenetic datasets, and identify candidate functional variants that may contribute to T2D. Using whole-genome sequencing of native and bisulfite-converted DNA (WGS and WGBS), I identifyied differentially methylated regions (DMRs) associated with disease, and genetic variants associated with methylation levels (mQTL). Integration of these data sets with existing mRNA-Seq data and reference chromatin state maps will produce the highest dimensional molecular profile of T2D to date, and yield valuable insights into mechanisms associated with T2D susceptibility and progression. Ultimately, this should advance the understanding of the tissue-specific genetic regulatory architecture of T2D, and may indicate novel therapeutic approaches that are more precise and personalized than those currently available.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Friday, March 26, 2021