Abstract
BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established. METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRS(CAD)) were quantified for each participant across 13 p-value thresholds (P(T) 0.5-5e(-8)). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS(CAD) was examined in relation to the BACS and the optimized P(T) was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS(CAD)-cognition associations. Multiple regression analyses examined PRS(CAD) under the optimal P(T) and medication burden in relation to the BACS composite and subtest scores. RESULTS: Higher PRS(CAD) was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRS(CAD). After controlling for PRS(CAD), a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029). CONCLUSIONS: Higher PRS(CAD) and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.