Characterizing rare copy number variants in schizophrenia: a clinical, cognitive, and neuroimaging study.

Abstract

Background: Schizophrenia is a highly heritable disorder affecting approximately 1 in 100 people in Australia and worldwide. The emerging picture is of common and rare genetic variants, as well as environmental factors, contributing to risk. One such rare variant is chromosomal microdeletions, especially large rare deletions. However, little is known about how these deletions affect the phenotype and confer risk for schizophrenia. Method: Clinical data (N=633), cognitive data (N=78), and neuroimaging data (VBM, DTI, & fMRI) (N=35) were collected on patients with schizophrenia with existing genetic information available from a large genome-wide association study (GWAS) pertaining to the presence of large, rare deletions and deletion burden in general. Results: Rare deletions were associated with reduced rates of cannabis abuse, later age at onset of psychosis, greater cognitive dysfunction, and structural (VBM and DTI) profiles intermediate to those identified between healthy controls and schizophrenia patients in general. Rare deletions were associated with reduced functional connectivity between prefrontal cortex and striatum and between regions in the default mode network as identified in rs-fMRI. Conclusions: Rare deletions affect the schizophrenia phenotype across clinical, cognitive, and neuroimaging domains, suggesting an important role in the developmental pathway towards psychosis. Further investigation is warranted, especially in larger samples.