The Impact of Copy Number Deletions on General Cognitive Ability and Ventricle Size in Patients with Schizophrenia and Healthy Control Subjects

Abstract

Background General cognitive ability is usually lower in individuals with schizophrenia, partly due to genetic influences. However, the specific genetic features related to general cognitive ability are poorly understood. Individual variation in a specific type of mutation, uncommon genetic deletions, has recently been linked with both general cognitive ability and risk for schizophrenia. Methods We derived measures of the aggregate number of “uncommon” deletions (i.e., those occurring in 3% or less of our combined samples) and the total number of base pairs affected by these deletions in individuals with schizophrenia (N = 79) and healthy controls (N = 110), and related each measure to the first principal component of a large battery of cognitive tests, a common technique for characterizing general cognitive ability. These two measures of mutation load were also evaluated for relationships with total brain gray matter, white matter, and lateral ventricle volume. Results The groups did not differ on genetic variables. Multivariate general linear models revealed a group (controls versus patients) by uncommon deletion number interaction, such that the latter variable was associated with lower general cognitive ability and larger ventricles in patients but not controls. Conclusions These data suggest that aggregate uncommon deletion burden moderates central features of the schizophrenia phenotype.

Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia

“…The finding of a negative correlation between IQ and deletion burden is consistent with a previous study by Yeo et al [4] but in the current study this was only significant for verbal IQ and not performance IQ. As performance IQ is more a measure of fluid intelligence and verbal IQ more a measure of crystallized intelligence, rare deletions may be affecting language capacity and ability to learn from experience to a greater extent than the capacity to understand and apply abstract non-verbal concepts in problem-solving.…”

“…However, this may be due to the inclusion of all deletions regardless of Page 4 of 38 A c c e p t e d M a n u s c r i p t 4 frequency and could explain the discrepancy between their findings and the findings of Yeo et al [4].…”

“…As the correlation between total deletion burden and current IQ is no longer significant when premorbid IQ is included in the model, it suggests that there is no further cognitive decline after the onset of psychosis attributable to total deletion burden. A further consistency with Yeo et al (2013) is the absence of a relationship with total grey and white matter volume. However, by investigating regional differences using VBM, we were able to identify several brain regions with grey-matter volumes significantly correlated with total deletion burden.…”

“…The twohit hypothesis [88] also argues that risk for schizophrenia is due to an additive effect of genetic risk variants, where two or more hits are required for the disease to manifest. As total deletion burden has no cognitive effect in healthy controls [4], it suggests that these deletions are affecting the phenotype only in the presence of other environmental or genetic variants. Although an in-depth examination of the deletions was beyond the scope of this study, the fact that disparate deletions converged on common endophenotypes suggests that they are likely having an effect on fundamental processes of neuronal functioning, Several neuronal models of schizophrenia have been proposed based on genetic findings, such as the dysfunctional synapse [89] or the NMDA glutamate receptor [90].…”

“…Recently, several studies have looked to characterize these deletions in schizophrenia. Using a liberal definition of uncommon deletions (<3% frequency), a recent study [4] found cognitive ability to be inversely correlated with deletion burden in patients but not healthy controls, suggesting an interaction between deletions and other schizophrenia associated genetic and environmental risk variants, affecting cognitive functioning. They also found deletion burden to be positively correlated with ventricle size offering evidence that deletions may be impacting structural phenotypes relevant for disease risk.…”