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

Rammos, Alexandros, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Hubbard, Leon, Walters, James ORCID: https://orcid.org/0000-0002-6980-4053, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862 and Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222 2023. Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia. Molecular Psychiatry 28 , pp. 2081-2087. 10.1038/s41380-023-02013-2

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Abstract

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 common and rare variants to school performance, and by implication cognitive function, in schizophrenia. Parental transmission of common alleles contributing to higher educational attainment (p value = 0.00015; OR = 2.63) and intelligence (p value = 0.00009; OR = 2.80), but not to schizophrenia, were associated with higher proband school performance. No significant effects were seen for non-transmitted parental common alleles. Probands with lower school performance 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. Among probands with lower school performance, those with damaging de novo coding variants in DD genes had a higher rate of comorbid mild intellectual disability (p value = 0.0002; OR = 15.6). Overall, we provide evidence for rare and common genetic contributions to school performance in schizophrenia. The strong effects for damaging de novo coding 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 common alleles for cognitive traits contributed to school performance in schizophrenia via indirect effects on the environment.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Nature Publishing Group
ISSN:	1359-4184
Funders:	MRC
Date of First Compliant Deposit:	28 February 2023
Date of Acceptance:	22 February 2023
Last Modified:	26 Oct 2023 14:02
URI:	https://orca.cardiff.ac.uk/id/eprint/157386

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