Rare copy number variations are associated with poorer cognition in schizophrenia

Leon Hubbard, Elliott Rees, Derek W Morris, Amy J Lynham, Alex L Richards, Antonio F Pardiñas, Sophie E Legge, Denise Harold, Stanley Zammit, Aiden C Corvin, Michael G Gill, Jeremy Hall, Peter Holmans, Michael C O'Donovan, Michael J Owen, Gary Donohoe, George Kirov, Andrew Pocklington, James T R Walters

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Background
Cognitive impairment in schizophrenia is a major contributor to poor outcomes yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and impact cognition in healthy populations but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods
General cognitive ability was measured using the MATRICS composite z-score in 875 schizophrenia cases, and in a replication sample of 519 schizophrenia cases using WAIS Full-Scale IQ. Using linear regression we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia enriched gene sets (loss of function intolerant or synaptic gene sets) were associated with cognitive impairment.

Results
23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than non-schizophrenia CNV carriers in discovery (β=-0.66, 95%CI = -1.31 to -0.01) and replication samples (β=-0.91, 95%CI =-1.71 to -0.11), and after meta-analysis (β=-0.76, 95%CI=-1.26 to -0.25, p=0.003). CNVs hitting loss of function intolerant genes were associated with lower cognition (β= -0.15, 95%CI=-0.29 to -0.001, p=0.048).

Conclusions
In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss of function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.
Original languageEnglish
JournalBiological Psychiatry
Publication statusAccepted/In press - 19 Nov 2020

Keywords

  • schizophrenia
  • copy number variation
  • cognition
  • schizophrenia CNV
  • CNV
  • general cognitive ability

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