Schizophrenia copy number variants and associative learning.
Schizophrenia copy number variants and associative learning.
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DOI：
10.1038/mp.2016.227
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发表时间：
2017-02
影响因子：
11
通讯作者：
Hall J
中科院分区：
文献类型：
--
作者：
Clifton NE;Pocklington AJ;Scholz B;Rees E;Walters JT;Kirov G;O'Donovan MC;Owen MJ;Wilkinson LS;Thomas KL;Hall J
大规模基因组研究在识别精神分裂症遗传风险变异方面取得了重大进展。这些研究的一个重要发现是，与对照组相比，精神分裂症病例的基因组拷贝数变异（CNV）负担增加。然而，这些 CNV 赋予精神分裂症症状风险的机制仍不清楚。一种可能性是，精神分裂症风险 CNV 会影响基本的联想学习过程，而这些过程的异常长期以来一直与该疾病有关。为了研究精神分裂症 CNV 中的基因是否影响联想学习的特定阶段，我们将人类遗传学与动物实验基因表达研究结合起来。在 11917 例精神分裂症病例和 16416 例对照样本中，我们研究了精神分裂症患者的 CNV 是否富含在联想记忆巩固、检索或消退过程中表达的基因。我们发现病例的 CNV 富含海马恐惧消退期间表达的基因，但巩固或恢复后表达的基因却没有。这些结果表明，CNV 会损害精神分裂症的抑制性学习，可能导致该疾病核心症状的发展。
Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.