title: Haplotypes of the D-Amino Acid Oxidase Gene Are Significantly Associated with Schizophrenia and Its Neurocognitive Deficits.
abstract: D-amino acid oxidase (DAO) has been reported to be associated with schizophrenia. This study aimed to search for genetic variants associated with this gene. The genomic regions of all exons, highly conserved regions of introns, and promoters of this gene were sequenced. Potentially meaningful single-nucleotide polymorphisms (SNPs) obtained from direct sequencing were selected for genotyping in 600 controls and 912 patients with schizophrenia and in a replicated sample consisting of 388 patients with schizophrenia. Genetic associations were examined using single-locus and haplotype association analyses. In single-locus analyses, the frequency of the C allele of a novel SNP rs55944529 located at intron 8 was found to be significantly higher in the original large patient sample (p = 0.016). This allele was associated with a higher level of DAO mRNA expression in the Epstein-Barr virus-transformed lymphocytes. The haplotype distribution of a haplotype block composed of rs11114083-rs2070586-rs2070587-rs55944529 across intron 1 and intron 8 was significantly different between the patients and controls and the haplotype frequencies of AAGC were significantly higher in patients, in both the original (corrected p < 0.0001) and replicated samples (corrected p = 0.0003). The CGTC haplotype was specifically associated with the subgroup with deficits in sustained attention and executive function and the AAGC haplotype was associated with the subgroup without such deficits. The DAO gene was a susceptibility gene for schizophrenia and the genomic region between intron 1 and intron 8 may harbor functional genetic variants, which may influence the mRNA expression of DAO and neurocognitive functions in schizophrenia.
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli 35053, Taiwan.|Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Sheng-Chang
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Hai-Gwo
authors.initials: HG
authors.lastname: Hwu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Cathy Shen-Jang
authors.initials: CS
authors.lastname: Fann
authors.affiliation: Institute of Bioinformatics, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Ueng-Cheng
authors.initials: UC
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Chien-Ching
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Chun-Chiang
authors.initials: CC
authors.lastname: Wen
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei 10051, Taiwan.
authors.forename: Jyy-Jih
authors.initials: JJ
authors.lastname: Tsai-Wu
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Tzung-Jeng
authors.initials: TJ
authors.lastname: Hwang
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Ming H
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Chen-Chung
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chien
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Chiu-Ping
authors.initials: CP
authors.lastname: Fang
authors.affiliation: Medical Genetics Research Center and Department of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY 13210, United States of America.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Harvard Institute of Psychiatric Epidemiology and Genetics, and Departments of Epidemiology and Psychiatry, Harvard University, Boston, Massachusetts, 02115, United States of America.|Institute of Behavioral Genomics, University of California San Diego, San Diego, California 92093, United States of America.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Wei J
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Chih-Min
authors.initials: CM
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D003605:D-Amino-Acid Oxidase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
chemical_list: D003605:D-Amino-Acid Oxidase