BACKGROUND: Genome wide association studies (GWAS) and candidate gene analyses have identified genetic variants and genes that may increase the risk for suicidal thoughts and behaviors (STBs). Important unresolved issues surround these tentative risk variants such as the characteristics of the associated genes and how they might elicit STBs. METHODS: Putative suicidality-related risk genes (PSRGs) were identified by comprehensive literature search and were characterized with respect to evolutionary conservation, participation in gene interaction networks and associated phenotypes. Evolutionary conservation was established with database searches and BLASTP queries, whereas gene-gene interactions were ascertained with GeneMANIA. We then examined whether mutations in risk-gene counterparts in produced a diminished motivation phenotype previously connected to suicide risk factors. RESULTS AND CONCLUSIONS: From the analysis, 105 risk-gene candidates were identified and found to be: 1) highly conserved during evolution, 2) enriched for essential genes, 3) involved in significant gene-gene interactions, and 4) associated with psychiatric disorders, metabolic disturbances and asthma/allergy. Evaluation of 17 mutant strains with loss-of-function/deletion mutations in PSRG orthologs revealed that 11 mutants showed significant evidence of diminished motivation that manifested as immobility in a foraging assay. Immobility was corrected in some or all of the mutants with clozapine, lithium and tricyclic antidepressant drugs. In addition, 5-HT2 receptor and muscarinic receptor antagonists restored goal-directed behavior in most or all of the mutants. These studies increase confidence in the validity of the PSRGs and provide initial clues about possible mechanisms that mediate STBs.