Abstract
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 (PRSSCZ) 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 PRSSCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was significantly associated with lower BACS scores (r = −0.17, p = 6.6 × 10−4 at PT = 1 × 10−4), but not with WRAT or EY. Among individuals with psychosis, PRSSCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRSSCZ 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.
Highlights
Schizophrenia is a debilitating psychiatric disorder that commonly involves severe cognitive deficits that compromise functional ability[1,2]
Both cognitive performance and psychotic disorders such as schizophrenia are heritable[12,13,14,15,16,17,18,19], and significant genetic overlap has been consistently reported between schizophrenia and some indicators of cognitive ability, such as general intelligence or processing speed[20,21,22,23,24,25,26]. It is still unclear how the genetic differences associated with schizophrenia influence cognitive function, and which domains of cognitive function are most associated with schizophrenia risk. Motivated by these earlier findings, we investigated the relationship between polygenic risk for schizophrenia—as defined by large constellations of common variants that associate with schizophrenia risk (PRSSCZ)—and three cognitive phenotypes in the Bipolar-Schizophrenia Network for Intermediate Phenotypes[27,28] (B-SNIP) cohort: (1) the Brief Assessment of Cognition in Schizophrenia (BACS)[29], which provides a composite score of current general cognitive function; (2) the Wide-Range Achievement Test (WRAT)[30,31,32] reading score, a measure of premorbid intellectual potential; and (3) educational attainment
Our work focused on the relationship between the common polygenic risk of schizophrenia and three cognitive measures that are phenotypically correlated (Fig. 2), but differentially associated (Fig S3) with psychosis-spectrum case status
Summary
Schizophrenia is a debilitating psychiatric disorder that commonly involves severe cognitive deficits that compromise functional ability[1,2]. Studies of clinically high-risk (CHR) groups have shown that people with attenuated psychotic symptoms were cognitively impaired compared to healthy controls (HC) and that, Shafee et al Translational Psychiatry (2018)8:78 within the CHR group, those that converted to a chronic psychotic disorder within one or 2 years of ascertainment displayed lower cognitive performance compared to those that did not convert[8,9,10,11]. Together these results indicate that cognitive deficits are significantly associated with risk of developing a psychotic illness
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