Chunk #27 — Results — Integrating Genetic and Network Data across Species to Inform GWA Discoveries — Identifying candidate susceptibility genes for coronary artery disease and LDL cholesterol levels.
To further elucidate the involvement of these genes in metabolic phenotypes associated with CAD, we examined Psrc1, Celsr2, and Sort1 in the context of the probabilistic, causal network constructed as described above for the Erbb3/Rps26 example. All three genes not only fell in the same subnetwork, they were all directly connected to the same gene, 2010200O16Rik, demonstrating that these genes are tightly co-regulated, possibly driven by common regulatory factors (Figure 3A). This same subnetwork also included genes like Tgfbr2, Pparg, Lpl, Ppm1l, and Alox5ap, all of which have been previously identified and validated as being associated with traits related to obesity, diabetes, cholesterol levels, and cardiovascular disease [25,31–33]. More generally, Psrc1 and Sort1 participate in a previously defined macrophage-enriched metabolic (MEM) subnetwork validated as causal for obesity-, diabetes-, and atherosclerosis-related traits [34]. In fact, the subnetwork depicted in Figure 3A is composed of 1,346 genes, with 226 of these genes overlapping the set of 1,406 genes composing the MEM subnetwork (82 would have been expected by chance). This 2.76-fold enrichment in this case is highly significant, with a Fisher exact test p = 8.20 × 10−47.
