Abstract 386: Identification of Genetic Regulatory Networks for Insulin Resistance in Multiple Populations of Diverse Ethnicities

Abstract

Insulin resistance (IR) is a critical pathogenic factor for highly prevalent modern cardiometabolic diseases, including coronary artery disease (CAD) and type 2 diabetes (T2D). However, the molecular circuitries underlying IR remain to be elucidated. The GENEticS of Insulin Sensitivity Consortium (GENESIS) conducted genome-wide association studies (GWAS) for direct measures of IR using euglycemic clamp or insulin suppression test. We sought to identify gene networks and their key intervening drivers for IR by performing a comprehensive integrative analysis leveraging GWAS data from seven GENESIS cohorts representing three ethnic groups - Europeans, Asians and Hispanics, along with expression quantitative trait loci, ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from IR relevant tissues. Integration of the multi-ethnic GWAS with diverse functional genomics information captured shared IR pathways and networks across ethnicities that are independent of body mass index, including GLUT4 translocation regulation, insulin signaling, MAPK signaling, interleukin signaling, extracellular matrix, branched-chain amino acids metabolisms, cell cycle, and oxidative phosphorylation. Further integration of these GWAS-informed IR processes with graphical gene networks uncovered potential key regulators including HADH, COX5A, VCAN and TOP2A , whose network neighbors are consistently enriched for the genetic association signals of IR across ethnicities, and show significant correlation with IR, fasting glucose and insulin levels in the transcriptomic-wide association data from a Hybrid Mouse Diversity Panel comprised of >100 strains fed with high-fat diet. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide new understanding of the pathways, gene networks and potential regulators contributing to IR. These results will also facilitate future functional investigations to unveil how DNA variations translate into IR.