Schizophrenia risk from complex variation of complement component 4.
Schizophrenia risk from complex variation of complement component 4.
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DOI：
10.1038/nature16549
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发表时间：
2016-02-11
期刊：
影响因子：
64.8
通讯作者：
McCarroll SA
中科院分区：
文献类型：
--
作者：
Sekar A;Bialas AR;de Rivera H;Davis A;Hammond TR;Kamitaki N;Tooley K;Presumey J;Baum M;Van Doren V;Genovese G;Rose SA;Handsaker RE;Schizophrenia Working Group of the Psychiatric Genomics Consortium;Daly MJ;Carroll MC;Stevens B;McCarroll SA
精神分裂症是一种遗传性脑部疾病，其致病机制尚不清楚。精神分裂症在群体水平上最强的遗传关联涉及主要组织相容性复合体（MHC）基因座的变异，但解释这一现象的基因和分子机制一直难以识别。我们在此表明，精神分裂症与 MHC 基因座的关联很大程度上源于补体成分 4 (C4) 基因的许多结构多样的等位基因。我们发现这些等位基因促进 C4A 和 C4B 表达水平差异很大，并且与精神分裂症相关，其与促进大脑中 C4A 更大表达的倾向成比例。人类 C4 蛋白定位于神经元突触、树突、轴突和细胞体。在小鼠中，C4 在出生后发育过程中介导突触消除。这些结果表明补体活动过度在精神分裂症的发展过程中，并可能有助于解释精神分裂症患者大脑中突触数量的减少。
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals affected with schizophrenia.