Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of polygenetic risk for schizophrenia (PRS_SCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychotic disorder patients, a measure of premorbid intelligence that is minimally affected by psychosis onset (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide single nucleotide polymorphism (SNP) data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRS_SCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRS_SCZ) was significantly associated with lower BACS scores (r = -0.17, p = 6.6 × 10^-4 at P_T = 1 × 10^-4), but not with WRAT or EY. Among individuals with psychosis, PRS_SCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRS_SCZ and WRAT in more than 4500 healthy subjects from the Philadelphia Neurodevelopmental Cohort. The association was again null (p > 0.3, N = 4511), suggesting that different cognitive phenotypes vary in their etiologic relationship with schizophrenia.