The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

BACKGROUND: Cognitiveimpairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitivephenotypes within schizophrenia cases. METHODS: We combined genetic and cognitivedata in 3034 schizophreniacases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognitionand PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognitionwas conducted in schizophreniacases. RESULTS: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognitionin those with schizophrenia. In contrast, there was no association between cognitionin schizophreniacases and PRS for schizophrenia(P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognitionin schizophreniacases is more strongly associated with PRS that index cognitivetraits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitivevariation within schizophreniaare at least partly independent from those that predispose to schizophreniadiagnosis itself. Our findings indicate that this cognitivevariation arises at least in part due to genetic factors sharedwith cognitiveperformance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.