title: Promoter variant rs2301228 on the neural cell adhesion molecule 1 gene confers risk of schizophrenia in Han Chinese.
abstract: BACKGROUND
  Schizophrenia is recognized as a disorder of the brain and neuronal connectivity. The neural cell adhesion molecule 1 (NCAM1) gene plays a crucial role in regulating neuronal connectivity.
  
  
  METHODS
  We conducted a two-stage association analysis on 17 NCAM1 SNPs in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Hunan Province: 986 patients and 1040 normal controls; replication sample from Yunnan Province: 564 cases and 547 healthy controls). Allele, genotype and haplotype frequencies were compared between case and control samples. Transcription factor binding site prediction and luciferase reporter assays were employed to assess the potential function of promoter SNPs. We detected developmental changes at the transcriptional level of NCAM1 during neuron differentiation in Macaca mulatta neural progenitor cells (NPC). Serum levels of NCAM1 were measured in 72 cases and 88 controls.
  
  
  RESULTS
  A promoter variant, rs2301228, was found to be associated with schizophrenia at the allelic level and was validated in a replication cohort. Luciferase reporter assays demonstrated that risk allele rs2301228-A significantly down-regulated NCAM1 gene transcription compared to the G-allele. Concordantly, schizophrenia patients had a significantly lower level of serum NCAM1 compared to healthy donors. During the NPC neuronal differentiation, NCAM1 mRNA was significantly increased, suggesting a critical role of this gene in neural development.
  
  
  CONCLUSIONS
  Our results provide direct evidence for NCAM1 as a susceptibility gene for schizophrenia, which offers support to a neurodevelopmental model and neuronal connectivity hypothesis in the onset of schizophrenia.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Mei-Sheng
authors.initials: MS
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Institute of Mental Health, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Hui-Zhen
authors.initials: HZ
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Deng-Feng
authors.initials: DF
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
authors.forename: Jicai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Coal Mine Mental Hospital of Yunnan Province, Honghe, Yunnan 652402, China.
authors.forename: Shuliang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
authors.forename: Xiu-Feng
authors.initials: XF
authors.lastname: Xu
authors.affiliation: Laboratory for Conservation and Utilization of Bio-resource & Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, Yunnan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Institute of Mental Health, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. Electronic address: ygyaozh@gmail.com.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
mesh_terms: D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics; D019002:CD56 Antigen / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000097:blood / Q000235:genetics*
chemical_list: D019002:CD56 Antigen; C522918:NCAM1 protein, human; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger
keywords: Association; ELISA; Luciferase assay; NCAM1; Replication; Schizophrenia