Scientists discover master regulator gene network behind complex psychiatric disorders

A study by the University of Barcelona has identified nearly 20 genes that could contribute to some people being more susceptible to depression, anxiety and traits such as irritability and neuroticism. These genes are regulated by the RBFOX1 gene, which acts as the central hub of a genetic network linked to several key processes in brain function. According to the researchers, this genetic overlap between different disorders and traits could help explain why they often appear together in the same person.

"These results provide a new insight into the biological mechanisms shared by depression and various associated disorders, and could contribute in the future to the development of more personalized biomarkers and treatments," explain the researchers who coordinated the study, Bru Cormand and Noèlia Fernández, from the Department of Genetics, Microbiology and Statistics at the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and the CIBER Area for Rare Diseases (CIBERER).

The study, published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry, also involved researchers from Goethe University Frankfurt (Germany).

A genetic "orchestra conductor"

The role of the RBFOX1 gene as a key regulator of a gene network would imply that this gene does not act alone or have a single effect, but rather functions "like a kind of orchestra conductor, helping to coordinate when and how many other genes involved in brain function are activated or processed," the researchers explain.

This finding is particularly relevant in complex psychiatric disorders, because conditions such as depression, anxiety or neuroticism do not usually depend on a single gene, but on the small, cumulative effects of hundreds or even thousands of genes. "If a central regulator such as RBFOX1 is altered, it could trigger a chain reaction across multiple processes simultaneously, such as neuronal development, communication between neurons and the regulation of neurotransmission, which would explain why these disorders often occur together," stress Cormand and Fernández.

This study integrates information from genome-wide association studies (GWAS), gene expression prediction in the brain, molecular network analysis and rare disease studies to prioritize genes that contribute to depression and, at least, one other related trait. "The study of rare diseases provides a complementary perspective, as it allows the identification of genes in which mutations of large effect produce phenotypes that include depression or anxiety. This reinforces the biological plausibility of the genes identified in common disorders and helps to prioritize relevant candidates," they note.

This comprehensive analysis identified 19 genes regulated by RBFOX1 that appear to be particularly relevant to depression and other traits frequently observed in patients. Among them, the researchers highlight, in addition to RBFOX1 as the central hub, three genes that also regulate the expression of other genes (SP4, TCF4 and PAX6), as well as the CADM2 gene. "In addition to being associated with depression, these genes have also been linked to other disorders: RBFOX1 is associated with several psychiatric disorders; CADM2 is involved in addictions and other psychiatric disorders; TCF4 has been linked to schizophrenia and insomnia, and both SP4 and PAX6 have been found to be altered in mouse models under stress," explain Cormand and Fernández.

Boosting personalized treatments

These results improve our understanding of the biological mechanisms involved in depression and related disorders and, in the future, could help identify risk biomarkers, enhance patient stratification and facilitate the development of treatments targeting specific molecular pathways. In this regard, the researchers point out that "intervening on shared mechanisms could simultaneously benefit various disorders that often co-occur in patients."

Despite the relevance of these findings, the researchers point out that they will need to be validated in other samples and that differences between men and women must be explored, given the higher prevalence of depression among women. They also propose carrying out functional experiments — laboratory studies that analyse how a specific gene acts and what effects its alteration has — on genes such as CADM2, which would allow us to determine which molecular mechanisms are involved in the origin of depression and the disorders associated with it.