Wen Zhang1, Mei-Sheng Xiao1, Shuang Ji2, Jinsong Tang3, Ling Xu4, Xiao Li4, Ming Li5, Hui-Zhen Wang6, Hong-Yan Jiang7, Deng-Feng Zhang4, Jicai Wang7, Shuliang Zhang8, Xiu-Feng Xu7, Li Yu9, Ping Zheng2, Xiaogang Chen3, Yong-Gang Yao10. 1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. 2. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. 3. Institute of Mental Health, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. 4. 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. 5. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. 6. 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. 7. Department of Psychiatry, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. 8. Coal Mine Mental Hospital of Yunnan Province, Honghe, Yunnan 652402, China. 9. Laboratory for Conservation and Utilization of Bio-resource & Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, Yunnan, China. 10. 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.
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.
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, schizophreniapatients 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: F Piras; M Schiff; C Chiapponi; P Bossù; M Mühlenhoff; C Caltagirone; R Gerardy-Schahn; H Hildebrandt; G Spalletta Journal: Transl Psychiatry Date: 2015-10-13 Impact factor: 6.222