Summary: Researchers have uncovered shared biological mechanisms across major psychiatric disorders by analyzing postmortem brain samples from the dorsolateral prefrontal cortex. Instead of looking at gene expression broadly, they zoomed in on the exon level—the building blocks that influence how proteins are made.
They found that gene activity differences were only apparent at this finer scale, not at the whole-gene level. The study revealed that disruptions in stress hormone regulation, dopamine signaling, and circadian rhythms are common to multiple disorders, including schizophrenia.
Key Facts:
- Exon-Level Insights: Psychiatric patients showed differences from healthy individuals only at the exon level, not the whole-gene level.
- Shared Pathways: Disruptions in circadian rhythm, cortisol release, and dopamine pathways were common across disorders.
- Toward Precision Psychiatry: Findings support classifying psychiatric disorders by biological mechanisms, not just symptoms.
Source: Max Planck Society
Researchers at the Max Planck Institute of Psychiatry, Helmholtz Munich 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.
This area of the brain 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.
What makes this study special: 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.
Differences at the exon level
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, leader of the Project Group Medical Genomics at the Max Planck Institute of Psychiatry, explains.
The team integrated different genetic data, including variations in individual base pairs of DNA (single nucleotide polymorphisms), 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.
About this genetics and mental health research news
Author: Anke Schlee
Source: Max Planck Society
Contact: Anke Schlee – Max Planck Society
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons” by Janine Knauer-Arloth et al. Translational Psychiatry
Abstract
Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons
Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive.
Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior.
This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach.
Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038).
Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders.
Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2–6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction.
Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level.
This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.
