Strong synaptic transmission impact by copy number variations in schizophrenia

Abstract

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

Fig. 1.

16q22.1 deletions found to be overrepresented in 35 independent schizophrenia cases. Affymetrix SNP and CN probe coverages are designated by blue lines in two separate tracks. Schizophrenia cases with deletions and their CNV call boundaries shown by red lines. The schizophrenia cases of our 1,735 cases population run on Affymetrix 6.0 are shown in comparison with our control cohort of 3,485 showing CNV overrepresentation in cases. ISC case and control CNV profiles also show overrepresentation. It is also noteworthy that duplications are conversely underrepresented in the schizophrenia cases (5) versus controls (27).