Polygenic risk scores differentiating schizophrenia from bipolar disorder are associated with premorbid intelligence in schizophrenia patients and healthy subjects.

Background Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, i.e., SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs. Methods Large-scale genome-wide association study (GWAS) datasets related to SCZ vs BD, childhood intelligence (CHI) and adulthood intelligence (n=12,441-282,014) were utilized to compute PGSs. PGSs derived from the GWASs were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated. Results High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (β=-0.17, p=4.12×10 -3). The correlation was still significant after adjusting for diagnostic status (β=-0.13, p=0.024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (p>0.05). PGSs for CHI were lower in SCZ patients than in HCs (R 2=0.025, p=0.025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline or the PGSs for SCZ-specific risk (p>0.05). Conclusions These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, i.e., crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ not via impaired impairments in intelligence.