The following is a summary of “Evolutionary conservation of putative suicidality-related risk genes that produce diminished motivation corrected by clozapine, lithium and antidepressants,” published in the January 2024 issue of Psychiatry by Ajayi et al.
Genome-wide association studies (GWAS) and candidate gene analyses have pinpointed genetic variations and genes linked to heightened susceptibility to suicidal thoughts and behaviors (STBs).
Researchers conducted a retrospective study to address unresolved issues regarding tentative risk variants, focusing on elucidating the characteristics of associated genes and their potential mechanisms in eliciting STBs.
They identified putative suicidality-related risk genes (PSRGs) through an extensive literature review and then characterized them based on evolutionary conservation, participation in gene interaction networks, and associated phenotypes. Evolutionary conservation was determined via database searches and BLASTP queries. At the same time, gene-gene interactions were assessed using GeneMANIA. They investigated mutations in counterparts of these risk genes in C. elegans, which led to a diminished motivation phenotype linked to suicide risk factors.
The results identified 105 risk-gene candidates who were highly conserved during evolution, enriched for essential genes, involved in significant gene-gene interactions, and associated with psychiatric disorders, metabolic disturbances, and asthma/allergy. Evaluating 17 mutant strains with loss-of-function/deletion mutations in PSRG orthologs revealed that 11 mutants exhibited significantly diminished motivation, leading to immobility observed in a foraging assay, which was alleviated in certain or all of the mutants through the administration of clozapine, lithium, and tricyclic antidepressant drugs. 5-HT2 receptor and muscarinic receptor antagonists restored goal-directed behavior in most or all mutants.
Investigators concluded that research strengthens the foundation for PSRGs and offers glimpses into potential mechanisms underlying STBs.
Source: frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1341735/full
