Polygenic burden of ubiquitin system genes in schizophrenia: focus on prenatal neurodevelopment

Schizophrenia (SZ) is a highly heritable psychiatric disorder with neurodevelopmental origins and a marked impact on cognition. Although alterations in the ubiquitin system have been reported in SZ, the contribution of common genetic variation within this system remains unclear. Using polygenic scores (PGS) analysis, we assessed the contribution of common SZ-associated variation within ubiquitin system genes (USG) to the disorder susceptibility and whether this contribution varies according to USG spatiotemporal brain expression patterns. We further explored the association of these PGS with cognitive performance. We defined a Gene Ontology-based panel of 1,450 autosomal USG (global USG panel; gUSG) and tested its enrichment for SZ-associated variation. We calculated the PGS of this panel in 183 individuals with SZ and 127 healthy controls (HC). BrainSpan data were used to stratify the gUSG into different panels by developmental stage (prenatal or postnatal) and brain region (prefrontal cortex and cerebellum). Cognitive evaluation was based on premorbid and current intelligence quotient (IQ), memory and executive function tests. USG were enriched for SZ-associated variation, and individuals with the disorder showed a higher polygenic burden within this system. The strongest associations involved USG expressed during prenatal development, particularly in the prefrontal cortex. Within SZ, the gUSG-PGS was associated with lower premorbid and current IQ, whereas the prenatal-prefrontal PGS was associated with poorer memory. Together, these findings support a role for USGs in the genetic architecture of SZ and suggest that common variation within this system may link genetic susceptibility to neurodevelopmental processes and cognitive heterogeneity in SZ. Keywords: Schizophrenia, Ubiquitin system, Polygenic scores, Cognition