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

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.

Rare coding variants in schizophrenia-associated genes affect generalised cognition in the UK Biobank

“…These variants therefore have effects on cognition that are not captured by tests of single domains of cognitive function. We also found that only the rarest alleles (those occurring in only one sample in our dataset, equating to a MAF of < 2.7x10 -6 ) in LoFi genes were significantly associated with g, thus supporting findings from other studies of cognition in UKBB 22 , as well as studies of cognition in schizophrenia [51][52][53] , that are consistent with the notion that damaging RCVs impacting generalised cognition are under strong selective constraint.…”

Socioeconomic status and severe mental disorders: a bidirectional multivariable Mendelian randomisation study

“…This is consistent with recent research suggesting that genetic liability to higher EA could affect health and social outcomes independently of educational milestones or changes in wages. 46 A combined liability-threshold model which includes putative rare variants with large effects 59 and involves potential gene-environmental interaction effects such as the stigma and discrimination associated with some diagnostic categories, 60 the disability associated with early symptoms and drug abuse, 51 61 the potential impact of isolation and social defeat 62 63 and a likely negative expectation effect towards SMD such as SCZ, 64 could provide more accurate estimates in the future.…”

Indicators of HSV1 Infection, ECM–Receptor Interaction, and Chromatin Modulation in a Nuclear Family with Schizophrenia

“…These studies indicate that the genetic underpinnings of SCZ are very complex and heterogeneous. One strategy to better understand the etiology of this disorder is through a family-based analysis of the contribution of rare and common genetic variants to the disorder with whole-exome sequencing (WES) [ 7 , 8 , 9 ].…”