title: Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci.
abstract: Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.
authors.affiliation: *To whom correspondence should be addressed; Flaum Eye Institute and Department of Ophthalmology, 601 Elmwood Avenue, Box 659, University of Rochester, Rochester, NY 14642, US; tel: 585-880-8814, fax: 585-276-2432, e-mail: xiongjian_luo@urmc.rochester.edu.
authors.forename: Xiongjian
authors.initials: X
authors.lastname: Luo
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
mesh_terms: D002843:Chromatin / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D056726:Genetic Association Studies / Q000379:methods*; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009434:Neural Pathways / Q000502:physiology; D009707:Nucleosomes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025941:Protein Interaction Mapping / Q000379:methods; D060066:Protein Interaction Maps / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D054928:Validation Studies as Topic
chemical_list: D002843:Chromatin; D009707:Nucleosomes
keywords: common molecular networks; enrichment; genetic heterogeneity; genome-wide association study; protein-protein interaction; schizophrenia susceptibility genes