Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia

Impaired cognition in schizophrenia is associated with worse functional outcomes. While genetic factors are known to contribute to variation in cognition in schizophrenia, few rare coding variants with strong effects have been identified, and the relative effects from de novo, inherited and non-transmitted alleles are unknown. We used array and exome sequencing data from 656 proband-parent trios to examine the contribution of rare and common variants to school performance, and by implication cognitive function, in schizophrenia. Probands who performed worse at school were enriched for damaging de novo coding variants in genes associated with developmental disorders (DD) (p-value = 0.00026; OR = 11.6). Damaging, ultra-rare coding variants in DD genes that were transmitted or non-transmitted from parents, had no effects on school performance. 13 probands had damaging de novocoding variants in DD genes, of whom 12 had lower school performance. Among probands with lower school performance, those with damaging de novocoding variants in DD genes had a higher rate of comorbid mild intellectual disability (p-value = 0.0002; OR = 15.6). Parental transmission of common genetic liability for educational attainment and intelligence, but not for schizophrenia, was associated with proband school performance, but no significant effects were seen for non-transmitted parental alleles. Overall, we provide evidence for rare and common genetic contributions to school performance in schizophrenia. The strong effects for damaging de novocoding variants in DD genes provide further evidence that cognitive impairment in schizophrenia has a shared aetiology with developmental disorders. Furthermore, we report no evidence in this sample that non-transmitted parental alleles for cognitive traits contributed to school performance in schizophrenia via indirect effects on the environment.