Luo Xiongjian, Huang Liang, Han Leng, Luo Zhenwu, Hu Fang, Tieu Roger, Gan Lin
Flaum Eye Institute and Department of Ophthalmology, University of Rochester, Rochester, NY; College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China;
First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China; Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China;
Schizophr Bull. 2014 Nov;40(6):1285-99. doi: 10.1093/schbul/sbu045. Epub 2014 Mar 24.
Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics.
精神分裂症是一种常见的精神障碍，具有高遗传性和强遗传异质性。常见疾病-常见变异假说预测，精神分裂症部分归因于常见的遗传变异。然而，最近的研究清楚地表明，拷贝数变异（CNV）在精神分裂症易感性中也起关键作用，并解释了一部分缺失的遗传性。尽管已经鉴定出许多CNV，但不同研究中受CNV影响的许多区域重叠性较差，并且尚不清楚被CNV破坏的基因是否会增加精神分裂症的风险。通过使用累积评分，我们系统地对精神分裂症中受CNV影响的基因进行了优先级排序。我们确定了8个经常被CNV破坏的顶级基因，包括NRXN1、CHRNA7、BCL9、CYFIP1、GJA8、NDE1、SNAP29和GJA5。将受CNV影响的基因与已知的精神分裂症易感性基因（来自先前的遗传连锁和关联研究）整合，发现许多被CNV破坏的基因也与精神分裂症相关。进一步的蛋白质-蛋白质相互作用（PPI）分析表明，受CNV影响的基因的蛋白质产物经常与已知的精神分裂症相关蛋白质相互作用。最后，将CNV优先级排序数据与遗传关联和PPI数据进行系统整合，确定了关键的精神分裂症候选基因。我们的结果提供了精神分裂症中受CNV影响的基因的全局概述，并揭示了精神分裂症中从头CNV的密集互连分子网络。尽管优先级最高的顶级基因代表了有希望的精神分裂症风险基因，但需要使用不同的优先级排序方法和独立样本进行进一步研究以证实这些发现。然而，已确定的关键候选基因可能在精神分裂症的发病机制中起重要作用，对这些基因的进一步功能表征可能为未来的治疗和诊断提供关键靶点。
