Haplotypes of the D-amino acid oxidase gene are significantly associated with schizophrenia and its neurocognitive deficits

Yu Li Liu, Sheng Chang Wang, Hai Gwo Hwu, Cathy Shen Jang Fann, Ueng Cheng Yang, Wei Chih Yang, Pei Chun Hsu, Chien Ching Chang, Chun Chiang Wen, Jyy Jih Tsai-Wu, Tzung Jeng Hwang, Ming H. Hsieh, Chen Chung Liu, Yi Ling Chien, Chiu Ping Fang, Stephen V. Faraone, Ming T. Tsuang, Wei J. Chen, Chih Min Liu

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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.

Original languageEnglish
Article numbere0150435
JournalPLoS ONE
Volume11
Issue number3
DOIs
StatePublished - Mar 2016

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