LARGE SCALE genomic analysis shows that shared genetic architecture underpins many psychiatric disorders, challenging traditional diagnostic boundaries and supporting a more biologically informed approach to psychiatric classification.
Understanding Genetic Overlap in Psychiatry
Psychiatric disorders frequently co-occur and show substantial genetic overlap, complicating efforts to define them as distinct clinical entities. This challenge is particularly evident for conditions such as schizophrenia and bipolar disorder, where diagnostic separation has long been debated. Although previous genomic studies have identified numerous pleiotropic loci influencing multiple disorders, the broader structure of shared and disorder specific genetic influences has remained unclear. To address this gap, researchers conducted an extensive genomic investigation across a wide range of psychiatric conditions.
Study Design and Genomic Analysis
The analysis integrated genetic association data from common variants across 14 childhood and adult-onset psychiatric disorders, encompassing more than 1,056,000 cases. Using a combination of advanced statistical and functional genomic approaches, investigators identified underlying genomic factors that explain shared genetic risk. These analyses revealed five latent genomic factors that together accounted for approximately 66% of the genetic variance observed across individual psychiatric disorders. In total, 238 pleiotropic loci were associated with these shared factors, highlighting the extent of common genetic liability across diagnoses.
Key Genetic Factors and Biological Pathways
Two of the identified factors were particularly prominent. One factor encompassed schizophrenia and bipolar disorder and demonstrated extensive polygenic overlap and strong local genetic correlation, with very few disorders specific loci. A second factor included major depression, post-traumatic stress disorder, and anxiety disorders, similarly showing high levels of shared genetic signal. Across all 14 disorders, shared genetic influences were enriched for broad biological processes such as transcriptional regulation. More specific biological pathways emerged at the level of individual factors. The schizophrenia bipolar disorder factor showed substantial enrichment in genes expressed in excitatory neurons, suggesting shared neurobiological mechanisms related to synaptic signalling. In contrast, the internalising disorder factor was associated with genes involved in oligodendrocyte biology, pointing towards differences in glial function and myelination.
Implications for Diagnosis and Treatment
These findings suggest that current psychiatric diagnostic categories may not fully reflect underlying neurobiological realities. A classification system informed by shared genetic and biological mechanisms could better capture the true structure of psychiatric illness. Such an approach may also guide therapeutic development by identifying targets relevant to commonly co-occurring conditions rather than isolated diagnoses. The study provides a strong genomic foundation for rethinking psychiatric nosology with regard to shared risk and comorbidity.
Reference
Grotzinger AD et al. Mapping the genetic landscape across 14 psychiatric disorders. Nature. 2026;649:406-15.
