Strong synaptic transmission impact by copy number variations in schizophrenia
Strong synaptic transmission impact by copy number variations in schizophrenia
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DOI：
10.1073/pnas.1000274107
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发表时间：
2010-06-08
影响因子：
11.1
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
--
作者：
Glessner, Joseph T.;Reilly, Muredach P.;Hakonarson, Hakon
精神分裂症是一种在青春期后期发病的精神疾病，其病因不明，其特征在于阳性和阴性症状以及认知缺陷。为了确定增加精神分裂症风险的拷贝数变异（CNV），我们对977例精神分裂症患者和2，000名欧洲血统的健康成年人进行了全基因组CNV分析，这些人用170万个探针进行了基因分型。在一个由758名精神分裂症患者和1,485名对照者组成的独立队列中对阳性结果进行了评估。在这些病例中，基因本体突触传递基因家族明显富集CNV（P = 1.5 × 10（-7））。其中，负责神经元兴奋的钙信号基因CACNA 1B和DOC 2A分别在16例和10例中缺失和重复。此外，RET和RIT 2，这两个ras相关基因的神经嵴发育的重要性，显着影响CNVs。RET缺失仅见于7例，而RIT 2缺失在精神分裂症患者中占多数。我们的研究结果表明，涉及突触传递过程的新的变化有助于精神分裂症的遗传易感性。
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.