{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T23:08:43Z","timestamp":1768000123254,"version":"3.49.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"S12","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Schizophrenia is a complex disease with multiple factors contributing to its pathogenesis. In addition to environmental factors, genetic factors may also increase susceptibility. In other words, schizophrenia is a highly heritable disease. Some candidate genes have been deduced on the basis of their known function with others found on the basis of chromosomal location. Individuals with multiple candidate genes may have increased risk. However it is not clear what kind of gene combinations may produce the disease phenotype. Their collective effect remains to be studied.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Most pathways except metabolic pathways are rich in protein-protein interactions (PPIs). Thus, the PPI network contains pathway information, even though the upstream-downstream relation of PPI is yet to be explored. Here we have constructed a PPI sub-network by extracting the nearest neighbour of the 36 reported candidate genes described in the literature. Although these candidate genes were discovered by different approaches, most of the proteins formed a cluster. Two major protein interaction modules were identified on the basis of the pairwise distance among the proteins in this sub-network. The large and small clusters might play roles in synaptic transmission and signal transduction, respectively, based on gene ontology annotation. The protein interactions in the synaptic transmission cluster were used to explain the interaction between the NRG1 and CACNG2 genes, which was found by both linkage and association studies. This working hypothesis is supported by the co-expression analysis based on public microarray gene expression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>On the basis of the protein interaction network, it appears that the NRG1-triggered NMDAR protein internalization and the CACNG2 mediated AMPA receptor recruiting may act together in the glutamatergic signalling process. Since both the NMDA and AMPA receptors are calcium channels, this process may regulate the influx of Ca<jats:sup>2+<\/jats:sup>. Reducing the cation influx might be one of the disease mechanisms for schizophrenia. This PPI network analysis approach combined with the support from co-expression analysis may provide an efficient way to propose pathogenetic mechanisms for various highly heritable diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-9-s12-s23","type":"journal-article","created":{"date-parts":[[2008,12,12]],"date-time":"2008-12-12T19:14:09Z","timestamp":1229109249000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A protein interaction based model for schizophrenia study"],"prefix":"10.1186","volume":"9","author":[{"given":"Pei-Chun","family":"Hsu","sequence":"first","affiliation":[]},{"given":"Ueng-Cheng","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Kuan-Hui","family":"Shih","sequence":"additional","affiliation":[]},{"given":"Chih-Min","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Yu-Li","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Hai-Gwo","family":"Hwu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2008,12,12]]},"reference":[{"issue":"5","key":"2728_CR1","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/s10897-005-1622-4","volume":"14","author":"J Austin","year":"2005","unstructured":"Austin J: Schizophrenia: an update and review. J Genet Couns 2005,14(5):329\u2013340. 10.1007\/s10897-005-1622-4","journal-title":"J Genet Couns"},{"issue":"3","key":"2728_CR2","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1136\/jmg.2005.030718","volume":"42","author":"N Craddock","year":"2005","unstructured":"Craddock N, O'Donovan MC, Owen MJ: The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005,42(3):193\u2013204. 10.1136\/jmg.2005.030718","journal-title":"J Med Genet"},{"issue":"5","key":"2728_CR3","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/sj.ejhg.5201587","volume":"14","author":"M Karayiorgou","year":"2006","unstructured":"Karayiorgou M, Gogos JA: Schizophrenia genetics: uncovering positional candidate genes. Eur J Hum Genet 2006,14(5):512\u2013519. 10.1038\/sj.ejhg.5201587","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"2728_CR4","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.cell.2006.03.032","volume":"125","author":"J Lim","year":"2006","unstructured":"Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, et al.: A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 2006,125(4):801\u2013814. 10.1016\/j.cell.2006.03.032","journal-title":"Cell"},{"issue":"21","key":"2728_CR5","doi-asserted-by":"publisher","first-page":"8685","DOI":"10.1073\/pnas.0701361104","volume":"104","author":"KI Goh","year":"2007","unstructured":"Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL: The human disease network. Proc Natl Acad Sci USA 2007,104(21):8685\u20138690. 10.1073\/pnas.0701361104","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"2728_CR6","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1073\/pnas.0237338100","volume":"100","author":"AW Rives","year":"2003","unstructured":"Rives AW, Galitski T: Modular organization of cellular networks. Proc Natl Acad Sci USA 2003,100(3):1128\u20131133. 10.1073\/pnas.0237338100","journal-title":"Proc Natl Acad Sci USA"},{"issue":"12","key":"2728_CR7","doi-asserted-by":"publisher","first-page":"e174","DOI":"10.1371\/journal.pcbi.0020174","volume":"2","author":"Y Qi","year":"2006","unstructured":"Qi Y, Ge H: Modularity and dynamics of cellular networks. PLoS Comput Biol 2006,2(12):e174. 10.1371\/journal.pcbi.0020174","journal-title":"PLoS Comput Biol"},{"issue":"6761 Suppl","key":"2728_CR8","doi-asserted-by":"publisher","first-page":"C47","DOI":"10.1038\/35011540","volume":"402","author":"LH Hartwell","year":"1999","unstructured":"Hartwell LH, Hopfield JJ, Leibler S, Murray AW: From molecular to modular cell biology. Nature 1999,402(6761 Suppl):C47\u201352. 10.1038\/35011540","journal-title":"Nature"},{"issue":"1","key":"2728_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/S0014-4827(02)00102-7","volume":"284","author":"DL Falls","year":"2003","unstructured":"Falls DL: Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003,284(1):14\u201330. 10.1016\/S0014-4827(02)00102-7","journal-title":"Exp Cell Res"},{"issue":"4","key":"2728_CR10","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1086\/342734","volume":"71","author":"H Stefansson","year":"2002","unstructured":"Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, et al.: Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002,71(4):877\u2013892. 10.1086\/342734","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2728_CR11","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/ajmg.b.20161","volume":"134B","author":"CM Liu","year":"2005","unstructured":"Liu CM, Hwu HG, Fann CS, Lin CY, Liu YL, Ou-Yang WC, Lee SF: Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families. Am J Med Genet B Neuropsychiatr Genet 2005,134B(1):79\u201383. 10.1002\/ajmg.b.20161","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"issue":"3","key":"2728_CR12","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S0959-4388(00)00210-5","volume":"11","author":"A Buonanno","year":"2001","unstructured":"Buonanno A, Fischbach GD: Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 2001,11(3):287\u2013296. 10.1016\/S0959-4388(00)00210-5","journal-title":"Curr Opin Neurobiol"},{"issue":"6","key":"2728_CR13","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/nrn2392","volume":"9","author":"L Mei","year":"2008","unstructured":"Mei L, Xiong WC: Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 2008,9(6):437\u2013452. 10.1038\/nrn2392","journal-title":"Nat Rev Neurosci"},{"issue":"7","key":"2728_CR14","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/nm0706-734","volume":"12","author":"GD Fischbach","year":"2006","unstructured":"Fischbach GD: Schizophrenia: signals from the other side. Nat Med 2006,12(7):734\u2013735. 10.1038\/nm0706-734","journal-title":"Nat Med"},{"issue":"1","key":"2728_CR15","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/sj.mp.4001558","volume":"10","author":"PJ Harrison","year":"2005","unstructured":"Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005,10(1):40\u201368. image 45. image 45. 10.1038\/sj.mp.4001558","journal-title":"Mol Psychiatry"},{"issue":"7","key":"2728_CR16","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1038\/nm1418","volume":"12","author":"CG Hahn","year":"2006","unstructured":"Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, et al.: Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006,12(7):824\u2013828. 10.1038\/nm1418","journal-title":"Nat Med"},{"issue":"3","key":"2728_CR17","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/0304-3940(80)90178-0","volume":"20","author":"JS Kim","year":"1980","unstructured":"Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmuller B: Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett 1980,20(3):379\u2013382. 10.1016\/0304-3940(80)90178-0","journal-title":"Neurosci Lett"},{"key":"2728_CR18","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1196\/annals.1300.020","volume":"1003","author":"JT Coyle","year":"2003","unstructured":"Coyle JT, Tsai G, Goff D: Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 2003, 1003: 318\u2013327. 10.1196\/annals.1300.020","journal-title":"Ann N Y Acad Sci"},{"issue":"6815","key":"2728_CR19","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1038\/35050030","volume":"408","author":"L Chen","year":"2000","unstructured":"Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA: Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 2000,408(6815):936\u2013943. 10.1038\/35050030","journal-title":"Nature"},{"issue":"5","key":"2728_CR20","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.neuron.2007.01.030","volume":"53","author":"C Bats","year":"2007","unstructured":"Bats C, Groc L, Choquet D: The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 2007,53(5):719\u2013734. 10.1016\/j.neuron.2007.01.030","journal-title":"Neuron"},{"issue":"4","key":"2728_CR21","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/sj.mp.4001012","volume":"7","author":"JA Badner","year":"2002","unstructured":"Badner JA, Gershon ES: Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002,7(4):405\u2013411. 10.1038\/sj.mp.4001012","journal-title":"Mol Psychiatry"},{"key":"2728_CR22","volume-title":"Biol Psychiatry","author":"YL Liu","year":"2008","unstructured":"Liu YL, Fann CS, Liu CM, Chen WJ, Wu JY, Hung SI, Chen CH, Jou YS, Liu SK, Hwang TJ, et al.: RASD2, MYH9, and CACNG2 Genes at Chromosome 22q12 Associated with the Subgroup of Schizophrenia with Non-Deficit in Sustained Attention and Executive Function. Biol Psychiatry 2008."},{"issue":"4","key":"2728_CR23","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/sj.mp.4000752","volume":"5","author":"T Li","year":"2000","unstructured":"Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, Collier DA: Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000,5(4):452. 10.1038\/sj.mp.4000752","journal-title":"Mol Psychiatry"},{"key":"2728_CR24","first-page":"7","volume":"12","author":"CH Chen","year":"2002","unstructured":"Chen CH: Generalized association plots: information visualization via iteratively generated correlation matrices. Statistica Sinica 2002, 12: 7\u201329.","journal-title":"Statistica Sinica"},{"issue":"1","key":"2728_CR25","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al.: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000,25(1):25\u201329. 10.1038\/75556","journal-title":"Nat Genet"},{"issue":"4","key":"2728_CR26","doi-asserted-by":"publisher","first-page":"R28","DOI":"10.1186\/gb-2003-4-4-r28","volume":"4","author":"BR Zeeberg","year":"2003","unstructured":"Zeeberg BR, Feng W, Wang G, Wang MD, Fojo AT, Sunshine M, Narasimhan S, Kane DW, Reinhold WC, Lababidi S, et al.: GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 2003,4(4):R28. 10.1186\/gb-2003-4-4-r28","journal-title":"Genome Biol"},{"issue":"3","key":"2728_CR27","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1097\/00041444-199400430-00006","volume":"4","author":"C Pariseau","year":"1994","unstructured":"Pariseau C, Gregor P, Myles-Worsley M, Holik J, Hoff M, Waldo M, Freedman R, Coon H, Byerley W: Schizophrenia and glutamate receptor genes. Psychiatr Genet 1994,4(3):161\u2013165. 10.1097\/00041444-199400430-00006","journal-title":"Psychiatr Genet"},{"issue":"3","key":"2728_CR28","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.ccr.2006.02.019","volume":"9","author":"HS Phillips","year":"2006","unstructured":"Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, et al.: Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006,9(3):157\u2013173. 10.1016\/j.ccr.2006.02.019","journal-title":"Cancer Cell"},{"issue":"12","key":"2728_CR29","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/nrd961","volume":"1","author":"A Butte","year":"2002","unstructured":"Butte A: The use and analysis of microarray data. Nat Rev Drug Discov 2002,1(12):951\u2013960. 10.1038\/nrd961","journal-title":"Nat Rev Drug Discov"},{"key":"2728_CR30","volume-title":"PhD thesis","author":"HJ Yau","year":"2006","unstructured":"Yau HJ: Ontogeny of the Neuregulin Receptor ErbB4 in the Rat Forebrain and Phenotypic Characterization of ErbB4-Deficienct Mice. PhD thesis. Taiwan: National Yang-Ming University; 2006."},{"issue":"3","key":"2728_CR31","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1093\/cercor\/13.3.252","volume":"13","author":"HJ Yau","year":"2003","unstructured":"Yau HJ, Wang HF, Lai C, Liu FC: Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cereb Cortex 2003,13(3):252\u2013264. 10.1093\/cercor\/13.3.252","journal-title":"Cereb Cortex"},{"issue":"1\u20133","key":"2728_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.schres.2006.05.023","volume":"86","author":"CJ Carter","year":"2006","unstructured":"Carter CJ: Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophr Res 2006,86(1\u20133):1\u201314. 10.1016\/j.schres.2006.05.023","journal-title":"Schizophr Res"},{"issue":"6543","key":"2728_CR33","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/376737a0","volume":"376","author":"S Lev","year":"1995","unstructured":"Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J: Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 1995,376(6543):737\u2013745. 10.1038\/376737a0","journal-title":"Nature"},{"issue":"1","key":"2728_CR34","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/S0169-328X(96)00195-7","volume":"44","author":"SL Eastwood","year":"1997","unstructured":"Eastwood SL, Burnet PW, Harrison PJ: GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study. Brain Res Mol Brain Res 1997,44(1):92\u201398. 10.1016\/S0169-328X(96)00195-7","journal-title":"Brain Res Mol Brain Res"},{"issue":"11","key":"2728_CR35","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003,13(11):2498\u20132504. 10.1101\/gr.1239303","journal-title":"Genome Res"},{"issue":"1","key":"2728_CR36","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/nar\/30.1.207","volume":"30","author":"R Edgar","year":"2002","unstructured":"Edgar R, Domrachev M, Lash AE: Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 2002,30(1):207\u2013210. 10.1093\/nar\/30.1.207","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"2728_CR37","doi-asserted-by":"publisher","first-page":"e15","DOI":"10.1093\/nar\/gng015","volume":"31","author":"RA Irizarry","year":"2003","unstructured":"Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP: Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003,31(4):e15. 10.1093\/nar\/gng015","journal-title":"Nucleic Acids Res"},{"issue":"21","key":"2728_CR38","doi-asserted-by":"publisher","first-page":"13902","DOI":"10.1073\/pnas.172511199","volume":"99","author":"E Schnell","year":"2002","unstructured":"Schnell E, Sizemore M, Karimzadegan S, Chen L, Bredt DS, Nicoll RA: Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci USA 2002,99(21):13902\u201313907. 10.1073\/pnas.172511199","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-9-S12-S23.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T23:26:30Z","timestamp":1630452390000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-9-S12-S23"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12]]},"references-count":38,"journal-issue":{"issue":"S12","published-print":{"date-parts":[[2008,12]]}},"alternative-id":["2728"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-9-s12-s23","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,12]]},"assertion":[{"value":"12 December 2008","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"S23"}}