Symptomatic glycerol kinase deficiency (GKD) is associated with episodic metabolic and central nervous system deterioration. We report here the first application of Weighted Gene Co-Expression Network Analysis (WGCNA) to investigate a knockout (KO) murine model of a human genetic disease. WGCNA identified networks and key hub transcripts from liver mRNA of glycerol kinase (Gyk) KO and wild type (WT) mice. Day of life 1 (dol1) samples from KO mice contained a network module enriched for organic acid metabolism before Gyk KO mice develop organic acidemia and die on dol3-4 and the module containing Gyk was enriched with apoptotic genes. Roles for the highly connected Acot, Psat and Plk3 transcripts were confirmed in cell cultures and subsequently validated by causality testing. We provide evidence that GK may have an apoptotic moonlighting role that is lost in GKD. This systems biology strategy has improved our understanding of GKD pathogenesis and suggests possible treatments.