Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvested 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtained genome-wide genotyping and gene expression measurements for a subset of 313. We built failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerged as a novel regulator whose network connectivity changed significantly between health and disease. Time-course RNA sequencing after PPP1R3A knock-down validated network-based predictions of metabolic pathway expression, increased cardiomyocyte size, and perturbed respiratory metabolism. Mice lacking PPP1R3A were protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify new cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a novel central protective regulator in heart failure.

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