Corvin A, McGhee K A, Murphy K, Donohoe G, Nangle J M, Schwaiger S, Kenny N, Clarke S, Meagher D, Quinn J, Scully P, Baldwin P, Browne D, Walsh C, Waddington J L, Morris D W, Gill M
Neuropsychiatric Genetics Group, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, James Street, Dublin 8, Ireland.
Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):949-53. doi: 10.1002/ajmg.b.30452.
The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675-13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required.
D-氨基酸氧化酶（DAO）信号通路与精神分裂症的发病机制有关。这可能是通过DAO对N-甲基-D-天冬氨酸（NMDA）功能的调节来介导的，而DAO又由DAO激活剂（DAOA，原称G72）激活。Chumakov等人（2002年；《美国国家科学院院刊》99：13675 - 13680）鉴定出了新的精神分裂症易感基因DAOA/G30，此后一些独立研究报告了DAOA和DAO基因与精神分裂症之间存在关联的证据。然而，至少有两项研究未能重复原始报告中描述的这些基因座之间的上位性相互作用，并且在每个基因座报道的相关等位基因/单倍型存在差异。在本研究中，我们对来自爱尔兰共和国的373例符合《精神疾病诊断与统计手册》第四版（DSM-IV）精神分裂症/分裂情感性障碍患者样本和812名对照进行了DAOA/G30和DAO基因座的关联和上位性分析。校正所进行的检验数量后，我们发现两个基因的标记与精神分裂症之间存在关联的证据：DAOA/G30（P = 0.005，比值比（OR）= 1.34（1.09，1.65））和DAO（P = 0.003，OR = 1.43（1.12，1.84））。数据表明，DAO（标记rs2111902）的关联证据比之前认识到的更为一致，特别是在白种人精神分裂症人群中。我们发现DAOA和DAO基因相关单核苷酸多态性（SNP）之间存在上位性相互作用，这有助于精神分裂症风险（OR = 9.3（1.4，60.5））。基于这些数据，需要对参与DAO信号传导的基因进行更系统的研究。
