Strong synaptic transmission impact by copy number variations in schizophrenia

作者：Joseph Glessner, Muredach P. Reilly, Cecilia E. Kim, Nagahide Takahashi, Anthony Albano, Cuiping Hou, Jonathan P. Bradfield, Haitao Zhang, Patrick Sleiman, James H. Flory, Marcin Imieliński, Edward C. Frackelton, Rosetta Chiavacci, Kelly Thomas, Maria Garris, F. George Otieno, Michael Davidson, Mark Weiser, Abraham Reichenberg, Kenneth L. Davis, Joseph I. Friedman, Thomas P. Cappola, Kenneth B. Margulies, Daniel J. Rader, Struan F.A. Grant, Joseph D. Buxbaum, Raquel E. Gur, Håkon Håkonarson · 发表于：Proceedings of the National Academy of Sciences · 年份：2010 · DOI：10.1073/pnas.1000274107 · 被引用次数：244 · 研究领域：Genomic variations and chromosomal abnormalities、Genomics and Rare Diseases、Genomics and Chromatin Dynamics

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.