Study Uncovers Biological Links Across Psychiatric Conditions
A new study highlights the role of circadian rhythm, cortisol regulation, and dopamine signaling in the development of depression, bipolar disorder, and schizophrenia. By using detailed genetic analyses at the exon level, researchers uncovered common biological mechanisms across these conditions. The findings pave the way for a shift toward classifying and treating psychiatric disorders based on underlying biology rather than symptoms alone.
Researchers at Helmholtz Munich, the Max Planck Institute of Psychiatry (MPI), and the University of Sydney identified biological mechanisms that are shared across psychiatric disorders. To do so, the team analyzed postmortem brain tissue samples from the dorsolateral prefrontal cortex (DLPFC). The DLPFC is the center for reasoning and emotions in the brain and is often implicated in psychiatric disorders. Samples from affected individuals, most of whom were schizophrenia patients, and healthy controls were included in the study.
The research team combined several different layers of genetic data. “In contrast to studies that look at gene expression as a whole, we analyzed the exon level to better understand the structure of the genes. This detailed approach gave us a better understanding of how genetic variation influences disease risk”, first author Karolina Worf explains.
Exons are the essential, information-containing segments of a gene. In addition to providing the blueprint for building proteins, they also determine which versions of a protein ultimately arise from a gene. This happens through alternative splicing, a process that occurs in over 95 percent of human genes.
Including the exon level in the analysis was an important step: While samples from psychiatric patients and healthy controls were not significantly different at the gene level, they were significantly different at the exon level. “The risk of developing a psychiatric disorder seems to therefore not just depend on what genes you have, but how your genes are expressed”, Janine Knauer-Arloth, researcher at the Institute of Computational Biology at Helmholtz Munich and leader of the Project Group Medical Genomics at the MPI, explains.
The team integrated different genetic data, including variations in individual base pairs of DNA (single nucleotide polymorphisms, or SNPs), rare genetic variants and polygenic risk scores, which summarize a person’s disease risk by aggregating all relevant genetic variants. This way, the researchers discovered disruptions in pathways related to the circadian rhythm, the release of the stress hormone cortisol, and the neurotransmitter dopamine — across all three included disorders.
These results show that psychiatric disorders share a common biological basis. In the long-term, this knowledge can help researchers to classify psychiatric disorders not only based on symptoms, but also based on biological mechanisms. This paradigm shift is significant a step towards more precise diagnoses and treatment.
Original Publication
Worf et al., 2025: Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons. Translational Psychiatry. DOI: 10.1038/s41398-025-03366-8
