Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms
Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms
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DOI：
10.1001/archgenpsychiatry.2010.107
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发表时间：
2010-09-01
影响因子：
--
通讯作者：
Ehrenreich, Hannelore
中科院分区：
文献类型：
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作者：
Begemann, Martin;Grube, Sabrina;Ehrenreich, Hannelore
背景：精神分裂症是一组异质性精神障碍的集合术语，其生物学基础仍然模糊。特别是，风险或候选基因变异复杂的精神分裂症phenotype.Objective的具体贡献在很大程度上是未知的：准备地面的一种新的“phepomics”的方法，一个独特的精神分裂症患者的数据库建立了GRAS（哥廷根研究协会精神分裂症），旨在允许关联的遗传信息与可量化的表型。由于突触功能障碍在精神分裂症中起着关键作用，复杂蛋白2基因（CPLX 2）在第一个基于表型的遗传关联研究（PGAS）的GRAS.Design：继一个经典的病例对照方法，我们分析了CPLX 2多态性的贡献离散的认知领域内的精神分裂症患者的人口。为了深入了解某些CPLX 2变异体如何影响基因表达和功能，研究了患者外周血单核细胞、CPLX无效突变小鼠和转染细胞。（马克斯·普朗克实验医学研究所）和遍布德国的23个精神病合作中心。由一个不变的研究者团队检查了1071名精神分裂症患者（DSM-IV），导致GRAS数据库中每个患者有3000多个表型数据点，和1079名可比较种族的健康对照受试者。主要结果测量：认知表现，包括执行功能，推理和语言学习/记忆。结果：六个单核苷酸多态性，分布在整个CPLX 2基因上，被发现与精神分裂症受试者的当前认知高度相关，但与病前智力仅轻微相关。相应地，在Cplx 2无效突变小鼠中，仅在青春期期间施加的轻微脑损伤的组合中获得显著的认知功能丧失，从而模拟精神分裂症的临床相关环境风险（“二次打击”）。在人类CPLX 2基因中，检测到6个认知相关单核苷酸多态性中的1个，即3'非翻译区的rs3822674，影响microRNA-498结合和基因表达。相同的标记与CPLX 2在外周血单核细胞，nuclearcells.Conclusions的差异表达：PGAS允许标识标记相关的临床/生物学性状。CPLX 2变异体调节转录后基因表达改变了精神分裂症患者当前的认知能力
Context: Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown.Objective: To prepare the ground for a novel "phepomics" approach, a unique schizophrenia patient database was established by GRAS (Gottingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes. Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenomics-based genetic association study (PGAS) of GRAS.Design: Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx-null mutant mice, and transfected cells were investigated.Setting: Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany.Participants: One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity.Main Outcome Measure: Cognitive performance including executive functioning, reasoning, and verbal learning/memory.Results: Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2-null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mono-, nuclear cells.Conclusions: The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.