Department of Psychiatry, National Taiwan University Hospital, Yun Lin Branch, Yunlin, Taiwan.
Biol Psychiatry. 2011 Jul 1;70(1):51-8. doi: 10.1016/j.biopsych.2011.02.033. Epub 2011 Apr 30.
A genome scan of Taiwanese schizophrenia families suggested linkage to chromosome 10q22.3. We aimed to find the candidate genes in this region.
A total of 476 schizophrenia families were included. Hierarchical clustering method was used for clustering families to homogeneous subgroups according to their performances of sustained attention and executive function. Association analysis was performed using family-based association testing and TRANSMIT. Candidate associated regions were identified using the longest significance run method. The relative messenger RNA expression level was determined using real-time reverse transcriptase polymerase chain reaction.
First, we genotyped 18 microsatellite markers between D10S1432 and D10S1239. The maximum nonparametric linkage score was 2.79 on D10S195. Through family clustering, we found the maximum nonparametric linkage score was 3.70 on D10S195 in the family cluster with deficits in attention and executive function. Second, we genotyped 79 single nucleotide polymorphisms between D10S1432 and D10S580 in 90 attention deficit and execution deficit families. Association analysis indicated significant transmission distortion for nine single nucleotide polymorphisms. Using the longest significance run method, we identified a 427-kilobase region as a significant candidate region, which encompasses nine genes. Third, we studied messenger RNA expression of these nine genes in Epstein-Barr virus-transformed lymphoblastic cells. In schizophrenic patients, there was significantly lower expression of ANXA7, PPP3CB, and DNAJC9 and significantly higher expression of ZMYND17.
ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes are potential candidate genes for schizophrenia, especially in patients with deficits in sustained attention and executive function. The responsible functional variants remained to be clarified.
对台湾精神分裂症家系的全基因组扫描提示染色体 10q22.3 与精神分裂症相关。我们旨在该区域寻找候选基因。
共纳入 476 个精神分裂症家系。采用层次聚类方法根据其持续注意力和执行功能的表现将家系聚类为同质亚组。采用基于家系的关联检验和 TRANSMIT 进行关联分析。采用最长显著连锁区间法确定候选关联区间。采用实时逆转录聚合酶链反应测定相对信使 RNA 表达水平。
首先，我们对 D10S1432 和 D10S1239 之间的 18 个微卫星标记进行基因分型。D10S195 上的最大非参数连锁得分（linkage score）为 2.79。通过家系聚类，我们发现注意力和执行功能缺陷的家系聚类上 D10S195 的最大非参数连锁得分（linkage score）为 3.70。其次，我们在 90 个注意力缺陷和执行功能缺陷家系中对 D10S1432 和 D10S580 之间的 79 个单核苷酸多态性进行基因分型。关联分析显示 9 个单核苷酸多态性存在显著的传递偏倚。采用最长显著连锁区间法，我们鉴定出一个 427 千碱基的显著候选区间，该区间包含 9 个基因。第三，我们研究了 Epstein-Barr 病毒转化的淋巴母细胞中这 9 个基因的信使 RNA 表达。在精神分裂症患者中，ANXA7、PPP3CB 和 DNAJC9 的表达明显降低，而 ZMYND17 的表达明显升高。
ANXA7、PPP3CB、DNAJC9 和 ZMYND17 基因是精神分裂症的潜在候选基因，尤其是在持续注意力和执行功能缺陷的患者中。有待阐明其负责的功能变异。
