Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

J.H. Thygesen, A. Presman, J. Harju-Seppanen, H. Irizar, R. Jones, K. Kuchenbaecker, K. Lin, B.Z. Alizadeh, I. Austin-Zimmerman, A. Bartels-Velthuis, A. Bhat, R. Bruggeman, W. Cahn, S. Calafato, B. Crespo-Facorro, L. de Haan, S.M.C. de Zwarte, M. Di Forti, A. Diez-Revuelta, J. HallM.H. Hall, C. Iyegbe, A. Jablensky, R. Kahn, L. Kalaydjieva, E. Kravariti, S. Lawrie, J.J. Luykx, I. Mata, C. McDonald, A.M. McIntosh, A. McQuillin, R. Muir, R. Ophoff, M. Picchioni, D.P. Prata, S. Ranlund, D. Rujescu, B.P.F. Rutten, K. Schulze, M. Shaikh, F. Schirmbeck, C.J.P. Simons, T. Toulopoulou, T. van Amelsvoort, N. van Haren, J. van Os, R. van Winkel, E. Vassos, M. Walshe, Elvira Bramon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
Original languageEnglish
Pages (from-to)5307-5319
Number of pages13
JournalMolecular Psychiatry
Issue number9
Early online date27 Jul 2020
Publication statusPublished - Sept 2021


  • 16P11.2
  • 16p11.2
  • RISK
  • ability
  • association
  • deficits
  • deletions
  • duplications
  • phenotype
  • risk
  • schizophrenia
  • verbal memory

Cite this