Rare copy number variants in individuals at clinical high risk for psychosis: Enrichment of synaptic/brain-related functional pathways

Am J Med Genet B Neuropsychiatr Genet. 2020 Mar;183(2):140-151. doi: 10.1002/ajmg.b.32770. Epub 2019 Nov 19.


Schizophrenia is a complex and chronic neuropsychiatric disorder, with a heritability of around 60-80%. Large (>100 kb) rare (<1%) copy number variants (CNVs) occur more frequently in schizophrenia patients compared to controls. Currently, there are no studies reporting genome-wide CNVs in clinical high risk for psychosis (CHR-P) individuals. The aim of this study was to investigate the role of rare genome-wide CNVs in 84 CHR-P individuals and 124 presumably healthy controls. There were no significant differences in all rare CNV frequencies and sizes between CHR-P individuals and controls. However, brain-related CNVs and brain-related deletions were significantly more frequent in CHR-P individuals than controls. In CHR-P individuals, significant associations were found between brain-related CNV carriers and attenuated positive symptoms syndrome or cognitive disturbances (OR = 3.07, p = .0286). Brain-related CNV carriers experienced significantly higher negative symptoms (p = .0047), higher depressive symptoms (p = .0175), and higher disturbances of self and surroundings (p = .0029) than noncarriers. Furthermore, enrichment analysis of genes was performed in the regions of rare CNVs using three independent methods, which confirmed significant clustering of predefined genes involved in synaptic/brain-related functional pathways in CHR-P individuals. These results suggest that rare CNVs might affect synaptic/brain-related functional pathways in CHR-P individuals.

Keywords: CNV; clinical high risk; enrichment analysis; psychosis; schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • DNA Copy Number Variations / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Psychotic Disorders / genetics*
  • Psychotic Disorders / metabolism
  • Risk Factors
  • Schizophrenia / genetics*

Grant support