title: Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies.
abstract: Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., "presynaptic nicotinic acetylcholine receptors", "signaling by insulin receptor"). Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1) located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy.
authors.affiliation: Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, China.|Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Chu
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Sun
authors.affiliation: College of Electronics and Information Engineering, Tongji University, Shanghai, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Yin
authors.affiliation: School of Computer and Information Technology and Beijing Key Lab of Traffic Data Analysis and Mining, Beijing Jiaotong University, Beijing, China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Liu
authors.affiliation: Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Computer and Information Technology and Beijing Key Lab of Traffic Data Analysis and Mining, Beijing Jiaotong University, Beijing, China.
authors.forename: Pengyao
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China.
authors.forename: Tiezheng
authors.initials: T
authors.lastname: Zheng
authors.affiliation: School of Computer and Information Technology and Beijing Key Lab of Traffic Data Analysis and Mining, Beijing Jiaotong University, Beijing, China.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Biomedical Engineering, Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, China.|Liaoning Provincial Key Laboratory of Cerebral Diseases, Institute for Brain Disorders, Dalian Medical University, Dalian, China.|Research Center for the Control Engineering of Translational Precision Medicine, Dalian University of Technology, Dalian, China.|State Key Laboratory of Fine Chemicals, Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian, China.
authors.forename: Changkai
authors.initials: C
authors.lastname: Sun
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D053263:Gene Regulatory Networks; D006801:Humans; D060066:Protein Interaction Maps
chemical_list: D000927:Anticonvulsants