Polygenic Risk Scores, School Achievement, and Risk for Schizophrenia: A Danish Population-Based Study

Studies have suggested that poor school achievement is associated with increased risk of schizophrenia; however, the possible genetic contribution to this association is unknown. We investigated the possible effect of the polygenic risk score (PRS) for schizophrenia (PRS_SCZ) and for educational attainment (PRS_EDU) on the association between school performance and later schizophrenia.

We conducted a case-cohort study on a Danish population-based sample born from 1987 to 1995 comprising 1470 individuals with schizophrenia and 7318 subcohort noncases. Genome-wide data, school performance, and family psychiatric and socioeconomic background information were obtained from national registers and neonatal biobanks. PRS_SCZ and PRS_EDU were calculated using discovery effect size estimates from a meta-analysis of 34,600 cases and 45,968 controls and 293,723 individuals.

Higher PRS_SCZ increased the risk (incidence rate ratio [IRR]: 1.28; 95% confidence interval [CI], 1.19-1.36), whereas higher PRS_EDU decreased the risk of schizophrenia (IRR, 0.87; 95% CI, 0.82-0.92) per standard deviation. Not completing primary school and receiving low school marks were associated with increased risk of schizophrenia (IRR, 2.92; 95% CI, 2.37-3.60; and IRR, 1.58; 95% CI, 1.27-1.97, respectively), which was not confounded by PRS_SCZ or PRS_EDU. Adjusting for social factors and parental psychiatric history, effects of not completing primary school and receiving low school marks were attenuated by up to 25% (IRR, 2.19; 95% CI, 1.75-2.73; and IRR, 1.39; 95% CI, 1.11-1.75, respectively). Increasing PRS_EDU correlated with better school performance (p < .01; R² = 7.6%). PRS_SCZ and PRS_EDU was significantly negatively correlated (r = -.31, p < .01).

The current PRS did not account for the observed association between primary school performance and risk of schizophrenia.