Psychiatry breakthrough: Genetic mapping reveals five key factors underlying 14 psychiatric disorders
Researchers have identified five fundamental genetic factors that explain the majority of genetic risk across 14 psychiatric conditions, based on DNA data from over one million people. The findings challenge current diagnostic boundaries and suggest psychiatric disorders arise from shared biological pathways that manifest differently across conditions, potentially informing more targeted therapeutic development.
An international team led by researchers from the University of Colorado Boulder and Massachusetts General Hospital has conducted the most comprehensive genomic analysis of psychiatric disorders to date, revealing that most genetic risk is shared amongst subsets of conditions rather than being unique to individual diagnoses.
Cross-disorder genetic architecture mapped
The study, published in Nature on 10 December 2025, analysed genetic data from 1,056,201 individuals with psychiatric disorders including schizophrenia, bipolar disorder, major depression, anxiety, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, obsessive-compulsive disorder, Tourette’s syndrome, anorexia nervosa, and substance use disorders.
Using advanced statistical methods, the researchers identified five genomic factors that collectively explained approximately 66% of the genetic variance across the disorders. “The genetic variation underpinning these conditions clusters into five broad categories, which cut across current diagnostic boundaries,” explained Dr Abdel Abdellaoui from Amsterdam University Medical Centre, who authored an accompanying commentary on the research.
The five factors comprised: a compulsive disorders factor (anorexia nervosa, obsessive-compulsive disorder, Tourette’s syndrome); a schizophrenia-bipolar factor; a neurodevelopmental factor (autism spectrum disorder, ADHD); an internalising disorders factor (major depression, PTSD, anxiety); and a substance use factor (alcohol, cannabis, nicotine and opioid dependence).
Shared genetic risk concentrated in specific pathways
The research team, led by Dr Andrew Grotzinger and Professor Jordan Smoller, identified 238 unique genetic loci associated with at least one of the five factors, including 48 novel genetic regions not previously linked to psychiatric disorders. Critically, they found that genetic variants shared across all disorders were enriched for broad biological processes such as transcriptional regulation, whilst more specific pathways emerged at the individual factor level.
“The shared genetic signal across the schizophrenia-bipolar factor was substantially enriched in genes expressed in excitatory neurons, whereas the internalising factor was associated with oligodendrocyte biology,” the authors reported in their paper. This suggests different brain cell types uniquely confer risk to more circumscribed subsets of disorders.
Functional analyses revealed that genes associated with psychiatric risk factors showed peak expression during foetal development, highlighting the importance of early neurodevelopmental processes. The team also found that genetic variants associated with the schizophrenia-bipolar factor showed positive associations with the non-cognitive component of educational attainment, suggesting that genetic variants increasing psychosis risk might also contribute to creativity and persistence.
Implications for diagnosis and treatment
The findings have important implications for psychiatric nosology and treatment development. Disorders clustering on the same genetic factor showed remarkably similar genetic profiles, with very few disorder-specific variants distinguishing them. For instance, major depression, PTSD and anxiety disorders (the internalising factor) demonstrated high genetic correlations and shared 88 regional genetic hotspots.
“Few genetic variants are unique to a single diagnosis, suggesting that the categories in the Diagnostic and Statistical Manual might be useful clinically but are seemingly arbitrary at a biological level,” the researchers noted. This observation supports ongoing debates about diagnostic boundaries, particularly between conditions like schizophrenia and bipolar disorder, where genomic methods have revealed that the majority of genetic signal is shared.
The study also identified 101 genomic regions with correlated effects across multiple disorders, including a particularly pleiotropic hotspot on chromosome 11 containing the NCAM1-TTC12-ANKK1-DRD2 gene cluster, which showed associations with eight different psychiatric conditions. Such findings could inform the development of therapeutics designed to treat commonly occurring comorbid presentations.
Limitations and future directions
The researchers acknowledged several limitations, noting that analyses were primarily restricted to individuals of European genetic ancestry due to limited availability of genome-wide association study data from other populations. Cross-ancestry analyses suggested findings may generalise better for some disorders (such as schizophrenia) than others (PTSD and major depression), emphasising the need for ancestrally diverse research.
Professor Smoller emphasised the significance of these findings: “This evidence should contribute substantially to ongoing debates regarding diagnostic boundaries between disorders and could inform the development of novel treatments targeting shared biological pathways.”
The research represents the third major study from the Psychiatric Genomics Consortium Cross-Disorder working group, with substantial increases in sample sizes compared to previous analyses. The team called for future research including more diverse populations and exploration of how these insights can guide therapeutic development for the substantial proportion of individuals affected by multiple psychiatric conditions throughout their lifetime.
Reference
Grotzinger, A. D., Werme, J., Peyrot, W. J., et. al. (2025). Mapping the genetic landscape across 14 psychiatric disorders. Nature. https://doi.org/10.1038/s41586-025-09820-3
