Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome

Abstract

Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression.

Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.

Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.

Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

Keywords: 22q11 Deletion Syndrome; DiGeorge Syndrome; Microdeletion; Psychosis; Schizophrenia; Structural Variants; Velocardiofacial Syndrome.

Figure 1. Gene interaction proximity network based on physical and pathway interactions

Circles correspond to genes: 22q11.2 deletion genes with significant connectivity (CLTCL1, P2RX6, RTN4R, and SEPT5, purple), genes with mouse abnormal nervous system phenotypes overlapped by duplications exclusively in the 22q11.2DS-schizophrenia group (red), and linker genes (gold). The initial sets comprised the four 22q11.2 deletion region genes with significant connectivity and the 39 genes overlapped by duplications found exclusively in schizophrenia subjects and within the nervous system phenotype gene-set. Important “linker” genes were identified by retrieving the top-25 interaction neighbours of these genes in GeneMANIA, using the same protein-protein interaction and pathway interaction networks used in the connectivity test, and then sub-setting to those found connected to at least two different bait genes and belonging to the nervous system phenotype gene-set (86 genes). Connections correspond to interaction proximity obtained from GeneMANIA, setting the limit to the top 50 interactors; the connection line thickness is proportional to the GeneMANIA score (22). The resulting network is visualized in Cytoscape (23). The network suggests the presence of four interaction clusters, characterized by the presence of one gene from the 22q11.2 deletion region with significant connectivity results and at least one schizophrenia-only duplication-related gene (see text for details).