*To whom correspondence should be addressed; Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia and North Metropolitan Health Service-Mental Health, Gascoyne House, John XXIII Avenue, Mt Claremont, WA 6010, Perth, Australia; tel: (08)9347-6439, fax: (08)9384-5128, e-mail:
Schizophr Bull. 2013 Nov;39(6):1252-60. doi: 10.1093/schbul/sbs110. Epub 2012 Nov 15.
Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level.
ZNF804A 基因内的遗传变异性最近被发现与精神分裂症和双相情感障碍有关，尽管该基因可能导致风险的途径在很大程度上仍不清楚。我们着手研究常见的 ZNF804A 变体是否会影响与精神病相关的中间表型，如依赖前额叶和额颞叶脑功能的认知表现、精神分裂症特质和减轻的精神病体验，在一个大型年轻男性人群中。使用所有 4 种可用的自评精神分裂症特质问卷和认知数据进行关联分析，这些数据是从雅典精神病倾向和精神分裂症发病率研究（ASPIS）中回顾性抽取的。对 1507 名接受军事训练入伍的健康年轻男性的 DNA 样本进行了 ZNF804A 基因座中 4 个先前研究的多态性标记的基因分型。单标记分析显示，2 个最近确定的候选精神分裂症易感性变异（rs1344706 和 rs7597593）与一个经过改进的阳性精神分裂症特质表型之间存在显著关联，该表型主要表现为自我评定的偏执/参照观念。与所有阳性但非阴性的精神分裂症特质相关因素都有明显的关联。ZNF804A 基因型对偏执的影响在单倍型水平上得到了证实。在持续注意力或工作记忆表现的中心指数上没有显著的关联。在这项研究中，ZNF804A 的变异与一个基于人群的自我评定的精神分裂症特质表型有关，该表型先前被认为优先反映精神病的遗传易感性，并被定义为一种倾向，即将即时环境中的中性社会线索和感知体验错误地解释为与个人相关和重要的信息。这表明，ZNF804A 遗传变异与精神分裂症有关，可能在普通人群中为临床精神病提供了一种新的风险途径。
