Pathway analysis was performed including genes with at least one SNP with a gene-based corrected p-value <0.05. Separate analyses were performed with gene sets obtained from the case-control (62 genes) and Sympcountadj (198 genes) models. The most remarkable pathways were identified from the case-control model. The first and third most significant pathways resulting from this analysis were calcium signaling (p=0.002, false discovery rate (FDR)=0.15, Figure 2) and synaptic long-term potentiation (LTP) (p=0.004, FDR=0.17, Figure 3), respectively. (The second most-significant canonical pathway (p=0.0024) captured genes that influence cardiac hypertrophy.) The Ca2+ signaling pathway was identified by significant associations in genes encoding calcineurin A (PPP3CA), calcium/calmodulin-dependent protein kinase II beta (CAMK2B), histone deacetyltransferase 9 (HDAC9), and cAMP responsive element binding protein 5 (CREB5). Ca2+ signaling is also critical to LTP; thus, this pathway emerged as significant in part due to associations with PPP3CA, CAMK2B, and CREB5 (Table 3). Reanalysis using the DAVID software revealed that the top gene ontology functional category was “calcium ion binding” (p=0.0089) and the top KEGG pathway was “LTP” (p=0.034). These pathways (complete list, Table S2 in Supplement 2) are identical to the pathways identified by IPA.
