Schizophrenia gene networks and pathways and their applications for novel candidate gene selection.
Schizophrenia gene networks and pathways and their applications for novel candidate gene selection.
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DOI：
10.1371/journal.pone.0011351
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发表时间：
2010-06-29
期刊：
影响因子：
3.7
通讯作者：
Zhao Z
中科院分区：
文献类型：
--
作者：
Sun J;Jia P;Fanous AH;van den Oord E;Chen X;Riley BP;Amdur RL;Kendler KS;Zhao Z
精神分裂症（SZ）是一种遗传性的复杂精神障碍。从众多的传统研究中，我们发现在寻找精神分裂症的致病基因方面取得了有限的成功。蛋白质相互作用网络和基于途径的分析可能为我们研究精神分裂症的分子机制提供另一种有效的方法。我们使用多维循证方法选择了一份精神分裂症候选基因（SZGenes）列表。在人类蛋白质相互作用组的背景下，研究了这些SZGenes编码的蛋白质的全局网络特性，而通过比较从人类相互作用组中提取的sz特异性网络和癌症特异性网络，研究了局部网络特性。相对于癌症基因，我们观察到SZGenes在整个人类相互作用组中传播的扰动往往具有中等程度和中等效率。这表明精神分裂症可能与癌症有不同的病理机制，尽管两者都是复杂的疾病。我们利用Ingenuity系统进行通路分析，在蛋白质相互作用网络、通路和文献综述的基础上构建了首个精神分裂症分子网络（SMN）。我们确定了SZGenes中过度代表的24条通路，并检查了它们的相互作用和串扰。我们观察到这些通路与神经发育、免疫系统和视黄酸X受体（RXR）有关。我们对SMN的检查表明，精神分裂症是一个由多种途径失调引起的动态过程。最后，我们应用网络/途径方法鉴定了新的候选基因，其中一些可以通过实验验证。这项研究首次全面回顾了精神分裂症候选基因的网络和通路特征。我们的初步结果表明，这种系统生物学方法可能证明有希望选择复杂疾病的候选基因。我们的发现对精神分裂症的分子机制以及其他潜在的精神疾病具有重要意义。
Schizophrenia (SZ) is a heritable, complex mental disorder. We have seen limited success in finding causal genes for schizophrenia from numerous conventional studies. Protein interaction network and pathway-based analysis may provide us an alternative and effective approach to investigating the molecular mechanisms of schizophrenia. We selected a list of schizophrenia candidate genes (SZGenes) using a multi-dimensional evidence-based approach. The global network properties of proteins encoded by these SZGenes were explored in the context of the human protein interactome while local network properties were investigated by comparing SZ-specific and cancer-specific networks that were extracted from the human interactome. Relative to cancer genes, we observed that SZGenes tend to have an intermediate degree and an intermediate efficiency on a perturbation spreading throughout the human interactome. This suggested that schizophrenia might have different pathological mechanisms from cancer even though both are complex diseases. We conducted pathway analysis using Ingenuity System and constructed the first schizophrenia molecular network (SMN) based on protein interaction networks, pathways and literature survey. We identified 24 pathways overrepresented in SZGenes and examined their interactions and crosstalk. We observed that these pathways were related to neurodevelopment, immune system, and retinoic X receptor (RXR). Our examination of SMN revealed that schizophrenia is a dynamic process caused by dysregulation of the multiple pathways. Finally, we applied the network/pathway approach to identify novel candidate genes, some of which could be verified by experiments. This study provides the first comprehensive review of the network and pathway characteristics of schizophrenia candidate genes. Our preliminary results suggest that this systems biology approach might prove promising for selection of candidate genes for complex diseases. Our findings have important implications for the molecular mechanisms for schizophrenia and, potentially, other psychiatric disorders.
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影响因子：
4.5
作者：
Riley, Brien;Kuo, Po-Hsiu;Maher, Brion S.;Fanous, Ayman H.;Sun, Jingchun;Wormley, Brandon;O'Neill, F. Anthony;Walsh, Dermot;Zhao, Zhongming;Kendler, Kenneth S.
通讯作者：
Kendler, Kenneth S.
影响因子：
64.8
作者：
Stefansson, Hreinn;Ophoff, Roel A.;Steinberg, Stacy;Andreassen, Ole A.;Cichon, Sven;Rujescu, Dan;Werge, Thomas;Pietilainen, Olli P. H.;Mors, Ole;Mortensen, Preben B.;Sigurdsson, Engilbert;Gustafsson, Omar;Nyegaard, Mette;Tuulio-Henriksson, Annamari;Ingason, Andres;Hansen, Thomas;Suvisaari, Jaana;Lonnqvist, Jouko;Paunio, Tiina;Borglum, Anders D.;Hartmann, Annette;Fink-Jensen, Anders;Nordentoft, Merete;Hougaard, David;Norgaard-Pedersen, Bent;Bottcher, Yvonne;Olesen, Jes;Breuer, Rene;Moeller, Hans-Jurgen;Giegling, Ina;Rasmussen, Henrik B.;Timm, Sally;Mattheisen, Manuel;Bitter, Istvan;Rethelyi, Janos M.;Magnusdottir, Brynja B.;Sigmundsson, Thordur;Olason, Pall;Mason, Gisli;Gulcher, Jeffrey R.;Haraldsson, Magnus;Fossdal, Ragnheidur;Thorgeirsson, Thorgeir E.;Thorsteinsdottir, Unnur;Ruggeri, Mirella;Tosato, Sarah;Franke, Barbara;Strengman, Eric;Kiemeney, Lambertus A.;Melle, Ingrid;Djurovic, Srdjan;Abramova, Lilia;Kaleda, Vasily;Sanjuan, Julio;de Frutos, Rosa;Bramon, Elvira;Vassos, Evangelos;Fraser, Gillian;Ettinger, Ulrich;Picchioni, Marco;Walker, Nicholas;Toulopoulou, Timi;Need, Anna C.;Ge, Dongliang;Yoon, Joeng Lim;Shianna, Kevin V.;Freimer, Nelson B.;Cantor, Rita M.;Murray, Robin;Kong, Augustine;Golimbet, Vera;Carracedo, Angel;Arango, Celso;Costas, Javier;Joensson, Erik G.;Terenius, Lars;Agartz, Ingrid;Petursson, Hannes;Nothen, Markus M.;Rietschel, Marcella;Matthews, Paul M.;Muglia, Pierandrea;Peltonen, Leena;St Clair, David;Goldstein, David B.;Stefansson, Kari;Collier, David A.
通讯作者：
Collier, David A.
影响因子：
--
作者：
Perala, Jonna;Suvisaari, Jaana;Lonnqvist, Jouko
通讯作者：
Lonnqvist, Jouko
影响因子：
3.5
作者：
Balendran, A;Hare, GR;Alessi, DR
通讯作者：
Alessi, DR
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y