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 to 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 gene 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 shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR , CAV1 , IGF1 and PCOLCE , 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 using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D. Author summary Cardiovascular disease (CVD) and type 2 diabetes (T2D) are two tightly interrelated diseases that are leading epidemics and causes of deaths around the world. Elucidating the mechanistic connections between the two diseases will offer critical insights for the development of novel therapeutic avenues to target both simultaneously. Because of the challenging complexity of CVD and T2D, involving numerous risk factors, multiple tissues, and multidimensional molecular alterations, few have attempted such an investigation. We herein report a comprehensive and in-depth data-driven assessment of the shared mechanisms between CVD and T2D by integrating genomics data from diverse human populations including African Americans, Caucasian Americans, and Hispanic Americans with tissue-specific functional genomics information. We identified shared pathways and gene networks informed by CVD and T2D genetic risks across populations, confirming the importance of well-established processes, as well as unraveling previously under-appreciated processes such as extracellular matrix, branched-chain amino acid metabolism, and neuronal system for both diseases. Further incorporation of tissue-specific regulatory networks pinpointed potential key regulators that orchestrate the biological processes shared between the two diseases, which were cross-validated using cell culture and mouse models. This study suggests potential new therapeutic targets that warrant further investigation for both CVD and T2D.
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