The blurred lines between conditions such as depression, anxiety and schizophrenia may finally have a genetic explanation.

A new study, applying advanced genomic statistical methods to data from over 1 million cases, reveals that the shared genetic risk across 14 psychiatric disorders can be boiled down to just 5 underlying factors.

Shared genetic risk is common in psychiatric disorders

Psychiatric disorders such as depression, anxiety and schizophrenia present a challenge in the clinic: they rarely occur alone. Comorbidity is common, meaning patients often meet the criteria for multiple disorders simultaneously – complicating diagnosis and treatment planning.

Current diagnostic manuals categorize these conditions based on visible symptoms, but the underlying biology remains largely unclear. This symptom-based approach struggles when different conditions appear to share biological roots.

Past work has highlighted that this overlap is rooted in genetics. A single gene variant can affect the risk for several conditions, a concept known as shared genetic risk. Previous cross-disorder analyses identified many genetic regions that influence multiple disorders. For highly debated diagnoses like schizophrenia and bipolar disorder, genomic methods showed that most genetic signals are actually shared.

Despite these findings, the full scope of these shared influences has remained poorly defined.

The new study aimed to tackle the issue by applying advanced statistical genetic analyses to an exceptionally large dataset.

Five genetic factors underlie 14 psychiatric disorders

The team applied genomic structural equation modeling to association data from 14 psychiatric disorders. This method acts like a powerful statistical sieve, filtering through millions of genetic variants to find hidden factors that cause conditions to cluster. They analyzed genetic data from 1,056,201 cases, spanning conditions from attention deficit hyperactivity disorder and anorexia to schizophrenia and various substance use disorders.

The analysis revealed 5 distinct genomic factors that collectively accounted for 66% of the genetic risk across all 14 disorders. These factors were named for the conditions they encompass: Compulsive, Schizophrenia/Bipolar (SB), Neurodevelopmental, Internalizing (which includes depression and anxiety) and Substance Use. Schizophrenia and bipolar disorder shared such a degree of underlying risk that they were grouped to form the single SB factor.

The team then worked to identify the biological mechanisms underpinning each factor by connecting the genomic data to specific brain cell types.

The SB factor was strongly linked to excitatory neurons, which are the signaling units in the brain, and the Internalizing factor showed a unique association with oligodendrocytes, the cells responsible for insulating nerve fibers.

They also identified 101 genomic regions, termed genetic “hotspots”, which influence multiple disorders simultaneously. One region on Chromosome 11 was associated with increased risk for 8 of the 14 disorders.

Treating shared genetic pathways for depression and anxiety

The identification of just five underlying genetic factors, which explain two-thirds of the genetic risk, strongly supports a move toward a “neurobiologically valid” classification system. Current manuals classify these conditions separately, but this study shows they share a genetic factor linked to specific biology, such as the oligodendrocyte pathways.

This shared architecture also opens up therapeutic potential. In the future, treatment could target these shared oligodendrocyte pathways, rather than attempting to treat distinct diagnoses with different symptom-based drugs. If disorders also share a genetic foundation, a drug proven effective for one condition might be successfully repurposed for others within the same genetic group.

However, the study had a heavy reliance on populations of European ancestry. The authors explicitly caution that genetic correlations, such as the overlap between PTSD and depression, are known to vary significantly across different ancestral groups. This ancestry bias limits the generalizability of the results, underscoring a persistent issue in large-scale genetics research.

While current diagnoses rely on observable symptoms, the future of psychiatry appears to be in treating the shared underlying genetic architecture. Achieving this goal fully, however, requires urgently expanding these genomic maps to include diverse global populations.

Reference: Grotzinger AD, Werme J, Peyrot WJ, et al. Mapping the genetic landscape across 14 psychiatric disorders. Nature. 2025. doi: 10.1038/s41586-025-09820-3

This article is a rework of a press release issued by Springer Nature. *Material has been edited for length and content. *