Department Anatomic Pathology, University of Barcelona, Barcelona, Spain.
Am J Med Genet B Neuropsychiatr Genet. 2010 Jul;153B(5):1052-9. doi: 10.1002/ajmg.b.31073.
In a previous linkage disequilibrium mapping study, in the 3' end of ARVCF, we identified one intronic SNP rs165849 and one haplotype block associated with schizophrenia and related disorders. The aim of the present study was to explore whether functional genetic variants in the exonic regions of ARVCF included in this haplotype block are responsible for the association observed. To achieve this objective (1) the nine exons included in this haplotype block were resequenced in a group of 242 patients with schizophrenia and related disorders (Case 1). The SNPs identified were genotyped in a hospital-based control group of 373 subjects (Control 1) and an association study was performed. (2) The SNPs showing significant association in this analysis were genotyped in a new group of 102 patients with schizophrenia and related disorders (Case 2) and in a new group of 111 healthy subjects (Control 2). Three dbSNPs (rs35219372, rs5993890, and rs165815) were identified when the nine exons of ARVCF were resequenced. rs165815 was associated with schizophrenia and related disorders (homozygote CC OR = 3.39, permutated P value = 0.02). When the groups of cases (1 and 2) and controls (1 and 2) were merged, the analysis confirmed the association observed (homozygote CC OR = 3.25 permutated P value = 0.02). Given the role of ARVCF proposed in the neurodevelopmental hypothesis, our results further support the view that chromosome 22 contains a susceptibility gene, possibly ARVCF. The functional variant rs165815, which affects a critical region of ARVCF, is a considerable source of the genetic variability associated with the risk of developing schizophrenia.
在之前的连锁不平衡图谱研究中，我们在 ARVCF 的 3' 端发现了一个内含子 SNP(rs165849)和一个与精神分裂症及相关疾病相关的单倍型块。本研究的目的是探讨该单倍型块中包含的 ARVCF 外显子区域的功能性遗传变异是否与观察到的关联有关。为了实现这一目标：（1）在一组 242 名精神分裂症及相关疾病患者（病例 1）中重新测序了包含在该单倍型块中的九个外显子。在一个基于医院的对照组（373 名受试者）中对鉴定出的 SNPs 进行基因分型，并进行关联研究。（2）对该分析中显示出显著关联的 SNPs 在一组新的 102 名精神分裂症及相关疾病患者（病例 2）和一组新的 111 名健康受试者（对照组 2）中进行基因分型。当重新测序 ARVCF 的九个外显子时，确定了三个 dbSNP（rs35219372、rs5993890 和 rs165815）。rs165815 与精神分裂症及相关疾病相关（纯合子 CC OR=3.39，置换 P 值=0.02）。当将病例组（1 和 2）和对照组（1 和 2）合并时，分析结果证实了观察到的关联（纯合子 CC OR=3.25，置换 P 值=0.02）。鉴于 ARVCF 在神经发育假说中提出的作用，我们的结果进一步支持了这样一种观点，即 22 号染色体包含一个易感基因，可能是 ARVCF。影响 ARVCF 关键区域的功能性变异体 rs165815 是与精神分裂症发病风险相关的遗传变异的重要来源。
