title: Two-stage replication of previous genome-wide association studies of AS3MT-CNNM2-NT5C2 gene cluster region in a large schizophrenia case-control sample from Han Chinese population.
abstract: Schizophrenia is a devastating psychiatric condition with high heritability. Replicating the specific genetic variants that increase susceptibility to schizophrenia in different populations is critical to better understand schizophrenia. CNNM2 and NT5C2 are genes recently identified as susceptibility genes for schizophrenia in Europeans, but the exact mechanism by which these genes confer risk for schizophrenia remains unknown. In this study, we examined the potential for genetic susceptibility to schizophrenia of a three-gene cluster region, AS3MT-CNNM2-NT5C2. We implemented a two-stage strategy to conduct association analyses of the targeted regions with schizophrenia. A total of 8218 individuals were recruited, and 45 pre-selected single nucleotide polymorphisms (SNPs) were genotyped. Both single-marker and haplotype-based analyses were conducted in addition to imputation analysis to increase the coverage of our genetic markers. Two SNPs, rs11191419 (OR=1.24, P=7.28×10(-5)) and rs11191514 (OR=1.24, P=0.0003), with significant independent effects were identified. These results were supported by the data from both the discovery and validation stages. Further haplotype and imputation analyses also validated these results, and bioinformatics analyses indicated that CALHM1, which is located approximately 630kb away from CNNM2, might be a susceptible gene for schizophrenia. Our results provide further support that AS3MT, CNNM2 and CALHM1 are involved with the etiology and pathogenesis of schizophrenia, suggesting these genes are potential targets of interest for the improvement of disease management and the development of novel pharmacological strategies.
authors.affiliation: Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China. Electronic address: fanglingguan@163.com.
authors.forename: Fanglin
authors.initials: F
authors.lastname: Guan
authors.affiliation: Department of Psychiatry, School of Medicine, Washington University, Saint Louis, MO, USA. Electronic address: t.zhang@wustl.edu.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
authors.forename: Dongke
authors.initials: D
authors.lastname: Fu
authors.affiliation: Xi'an Mental Health Center, Xi'an, China.
authors.forename: Huali
authors.initials: H
authors.lastname: Lin
authors.affiliation: Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Forensic Psychiatry, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Chen
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics; D016022:Case-Control Studies; D027682:Cation Transport Proteins; D015331:Cohort Studies; D019295:Computational Biology; D016213:Cyclins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics*; D005810:Multigene Family; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C530077:CALHM1 protein, human; C558175:CNNM2 protein, human; D015220:Calcium Channels; D027682:Cation Transport Proteins; D016213:Cyclins; D008562:Membrane Glycoproteins; D008780:Methyltransferases; C505756:AS3MT protein, human; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human
keywords: AS3MT; CNNM2; Common variants; NT5C2; Schizophrenia