Researchers analyzed genome-wide association study data from more than 1 million participants across 14 psychiatric disorders to characterize shared and disorder-specific genetic risk. The analysis, published in Nature, included schizophrenia, bipolar disorder, major depression, anxiety disorders, post-traumatic stress disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, obsessive–compulsive disorder, Tourette syndrome, anorexia nervosa, and alcohol, nicotine, opioid, and cannabis use disorders. Most analyses were conducted in participants of European-like genetic ancestry due to limited sample sizes and statistical power.

Using linkage disequilibrium score regression and genomic structural equation modeling, the researchers identified widespread genetic overlap across disorders. A five-factor model provided the best fit to the data, explaining an average of about 66% of the genetic variance within individual disorders.

The factors reflected shared genetic liability among groups of conditions:

1. Schizophrenia–bipolar disorder factor – defined by schizophrenia and bipolar disorder
2. Internalizing disorders factor – defined by major depression, anxiety, and post-traumatic stress disorder
3. Neurodevelopmental factor – defined by autism spectrum disorder, attention-deficit/hyperactivity disorder, and Tourette syndrome
4. Compulsive disorders factor– defined by anorexia nervosa, obsessive-compulsive disorder, and Tourette syndrome
5. Substance use disorders factor - defined by alcohol, cannabis, opioid, and nicotine use disorders

Disorders loading on the same factor showed high genome-wide and regional genetic correlations (with some pairs exceeding 0.8), whereas disorders loading on different factors were more likely to show divergent genetic effects.

Multivariate genome-wide analyses identified 238 loci associated with 1 or more of the 5 factors, including 27 broadly pleiotropic loci affecting multiple factors. In addition, case–case analyses identified 412 loci that differentiated disorders belonging to different factors.

Regional analyses highlighted 101 genomic regions with significant local genetic correlations, including a region on chromosome 11 encompassing the NCAM1–TTC12–ANKK1–DRD2 gene cluster that showed shared associations across 8 disorders.

Functional annotation of factor-associated loci indicated that genetic risk shared across disorders was enriched in genes involved in broad biological processes such as gene regulation, with higher expression during fetal and early brain development. More specific enrichment patterns were observed at the factor level.

Loci associated with the schizophrenia–bipolar disorder factor were enriched in genes expressed in excitatory neuronal populations, including hippocampal and cortical subtypes. Loci associated with the internalizing disorders factor showed enrichment in glial cell types, particularly oligodendrocytes and their precursor cells, in adult brain tissue. This factor also showed enrichment in excitatory neurons in fetal brain, though less extensively than the schizophrenia–bipolar factor.

The p-factor—a higher-order general psychopathology factor loading on all five lower-order factors—was most strongly linked to traits like neuroticism, stress sensitivity, and loneliness.

These findings challenge current diagnostic boundaries, as disorders like schizophrenia and bipolar disorder share most of their genetic signal. The distinct biological pathways identified may inform therapeutics targeting shared mechanisms underlying commonly co-occurring conditions.

The findings were consistent across multiple analytic approaches, including global and local genetic correlation analyses, multivariate genome-wide association studies, and expression-based enrichment methods. The study had constraints related to variability in sample sizes across disorders. Future research incorporating ancestrally diverse populations will be essential to determine how well these findings generalize across global populations.

Full disclosures can be found in the published study. 

Source: Nature