Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States

by Le Shu, Kei Hang K. Chan, Guanglin Zhang, Tianxiao Huan, Zeyneb Kurt, Yuqi Zhao, Veronica Codoni, David-Alexandre Tr égouët, Cardiogenics Consortium , Jun Yang, James G. Wilson, Xi Luo, Daniel Levy, Aldons J. Lusis, Simin Liu, Xia Yang Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought t o identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific ge ne network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shar ed pathogenic processes for both diseases. Further, we uncovered 15 key drivers includingHMGCR,CAV1,IGF1 andPCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers usingin vitro siRNA knockdown,in vivo gene knockout, and tw...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research