Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia
Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia
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DOI：
10.1126/science.1155174
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发表时间：
2008-04-25
期刊：
影响因子：
56.9
通讯作者：
Sebat, Jonathan
中科院分区：
文献类型：
--
作者：
Walsh, Tom;McClellan, Jon M.;Sebat, Jonathan
精神分裂症是一种破坏性的神经发育障碍，其遗传影响仍然难以捉摸。我们假设个别罕见的结构变异有助于疾病。微缺失和微重复>100个重复酶通过微阵列比较基因组杂交从150名精神分裂症患者和268名祖先匹配的对照组的基因组DNA中鉴定。所有变体均通过高分辨率平台进行验证。新的基因缺失和重复存在于5%的对照组中，而15%的病例和20%的年轻发病病例中，两者都有非常显著的差异。这种关联在儿童期发作的精神分裂症患者中与其父母相比是独立重复的。在病例中，突变不成比例地破坏了控制神经发育的信号网络的基因，包括神经调节蛋白和谷氨酸途径。这些结果表明，多个单独的罕见突变改变神经发育途径中的基因有助于精神分裂症。
Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high- resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young- onset cases, both highly significant differences. The association was independently replicated in patients with childhood- onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.