Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals

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 = 1,459) 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 life-span indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.