Exploring the role of CAG repeats in HTT, ATXN1 and ATXN2 genes in the genetic architecture of mental disorders: schizophrenia and bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BD) are complex psychiatric disorders with partially overlapping genetic architectures and shared features with neurodegenerative diseases. Short tandem repeats (STRs), particularly CAG expansions in HTT , ATXN1 and ATXN2 , are established causes of neurodegenerative disorders, yet their role as genetic modifiers in major mental disorders remains poorly understood. We analysed CAG repeat sizes in a cohort of 1,604 individuals, including 234 SCZ patients, 329 BD patients and 1,041 healthy controls. Repeat lengths were determined by fluorescent PCR and capillary electrophoresis, and associations with disease risk and clinical phenotypes were evaluated using non-parametric tests, multinomial logistic regression and survival analyses. Intermediate HTT alleles were more frequent in BD type I compared with controls (8.8% vs 4.4%, p = 0.033), whereas ATXN1 intermediate alleles were less frequent in SCZ than in BD (4.7% vs 11.2%, p = 0.02). Although overall differences in repeat size were modest, ATXN2 CAG length showed consistent shifts across diagnostic groups, with slightly larger repeats in BD and SCZ than in controls. Multinomial models identified the ATXN2 long allele as associated with disease risk with a non-linear effect. Intermediate ATXN2 alleles were also associated with shorter disease duration in BD (p = 0.00048). Functional enrichment analysis revealed convergence of these genes with SCZ- and BD-related networks involved in synaptic function and RNA metabolism. These findings support a role for CAG repeat variation as a genetic modifier influencing susceptibility and clinical trajectories in psychiatric disorders.