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


Jagannath, Vinita; Grünblatt, Edna; Theodoridou, Anastasia; Oneda, Beatrice; Roth, Alexander; Gerstenberg, Miriam; Franscini, Maurizia; Traber‐Walker, Nina; Correll, Christoph U; Heekeren, Karsten; Rössler, Wulf; Rauch, Anita; Walitza, Susanne (2020). Rare copy number variants in individuals at clinical high risk for psychosis: Enrichment of synaptic/brain‐related functional pathways. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 183(2):140-151.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
04 Faculty of Medicine > Psychiatric University Hospital Zurich > Department of Child and Adolescent Psychiatry
04 Faculty of Medicine > Neuroscience Center Zurich
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Genetics(clinical), Cellular and Molecular Neuroscience, Psychiatry and Mental health
Language:English
Date:1 March 2020
Deposited On:08 Jan 2020 09:29
Last Modified:07 Feb 2020 02:04
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1552-4841
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/ajmg.b.32770
PubMed ID:31742845

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