Polygenic risk for schizophrenia is associated with white matter microstructure, cognitive and mental health

Schizophrenia is highly heritable, and polygenic risk score for schizophrenia (PRS_SCZ) has been associated with brain and behavior in healthy populations. However, the full associations of PRS_SCZ with brain white matter microstructure and cognitive and mental health outcomes, the potential effects of sex and areal deprivation on these associations, and the mediation of white matter microstructure for the associations between PRS_SCZ and behavioral outcomes remain largely unknown. In up to 300,000 participants from the UK Biobank, we investigated the associations of PRS_SCZ with eight white matter microstructure metrics of 48 tracts and 14 cognitive and mental health phenotypes, and we further tested the moderation of sex and index of multiple deprivation (IMD) on these associations and the mediation of brain white matter phenotypes for the associations between PRS_SCZ and behavioral outcomes. We found that higher PRS_SCZ was associated with decreased white matter integrity in 26 tracts, such as cingulum, corona radiata, and fornix. We also found that higher PRS_SCZ was associated with poorer mental health and worse cognitive performance. These associations were not significantly moderated by sex and IMD. Causal mediation analyses revealed that these adverse effects of PRS_SCZ on cognitive and mental health outcomes were partially mediated by brain white matter phenotypes. These results indicate that genetic risk for schizophrenia affects the integrity of white matter tracts, which may account for its adverse effects on cognitive and mental health outcomes.