Abstract
Polygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife, and late-life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25–100 years (N = 1459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the lifespan indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.
Highlights
Schizophrenia is a severe neuropsychiatric disorder that affects about 1% of the population [1, 2]
The effect of schizophrenia polygenic risk score (PRS) on cognition composite at baseline can be found in Supplementary Table 3, showing that the variance in cognitive test performance explained by schizophrenia PRS is largest for the PRS calculated with a p-value threshold ≤1, which was used for subsequent analyses
Using a large sample of healthy individuals, we found a robust interaction effect between schizophrenia PRS and sex on cognitive ability
Summary
Schizophrenia is a severe neuropsychiatric disorder that affects about 1% of the population [1, 2]. Evidence from studies reporting a link between poor school performance and risk of developing schizophrenia later in life [8, 9] supports the possibility that the cognitive deficits in schizophrenia patients may arise due to developmental causes already at young age [10] It is not known if schizophrenia genetics is related to school performance in the general population. Sex differences in relation to cognitive phenotypes were typically not reported in past genetic studies of schizophrenia [34, 36,37,38,39], but a recent study suggests male-specific effects of schizophrenia PRS on memory in healthy older adults [40]. This method uses PCA to gather the maximum variation from PRSs calculated across the 10 p-value thresholds in a single principal component and avoids multiple testing without suffering loss of power [52]
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