Choudhury Khalid, McQuillin Andrew, Puri Vinay, Pimm Jonathan, Datta Susmita, Thirumalai Srinivasa, Krasucki Robert, Lawrence Jacob, Bass Nicholas J, Quested Digby, Crombie Caroline, Fraser Gillian, Walker Nicholas, Nadeem Haitham, Johnson Sophie, Curtis David, St Clair David, Gurling Hugh M D
Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, W1T 4JF, UK.
Am J Hum Genet. 2007 Apr;80(4):664-72. doi: 10.1086/513475. Epub 2007 Mar 1.
Previous linkage analyses of families with multiple cases of schizophrenia by us and others have confirmed the involvement of the chromosome 11q22-24 region in the etiology of schizophrenia, with LOD scores of 3.4 and 3.1. We now report fine mapping of a susceptibility gene in the 11q22-24 region, determined on the basis of a University College London (UCL) sample of 496 cases and 488 supernormal controls. Confirmation was then performed by the study of an Aberdeen sample consisting of 858 cases and 591 controls (for a total of 2,433 individuals: 1,354 with schizophrenia and 1,079 controls). Seven microsatellite or single-nucleotide polymorphism (SNP) markers localized within or near the FXYD6 gene showed empirically significant allelic associations with schizophrenia in the UCL sample (for D11S1998, P=.021; for rs3168238, P=.009; for TTTC20.2, P=.048; for rs1815774, P=.049; for rs4938445, P=.010; for rs4938446, P=.025; for rs497768, P=.023). Several haplotypes were also found to be associated with schizophrenia; for example, haplotype Hap-F21 comprising markers rs10790212-rs4938445-rs497768 was found to be associated with schizophrenia, by a global permutation test (P=.002). Positive markers in the UCL sample were then genotyped in the Aberdeen sample. Two of these SNPs were found to be associated with schizophrenia in the Scottish sample (for rs4938445, P=.044; for rs497768, P=.037). The Hap-F21 haplotype also showed significant association with schizophrenia in the Aberdeen sample, with the same alleles being associated (P=.013). The FXYD6 gene encodes a protein called "phosphohippolin" that is highly expressed in regions of the brain thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiological requirements of the tissue. Etiological base-pair changes in FXYD6 or in associated promoter/control regions are likely to cause abnormal function or expression of phosphohippolin and to increase genetic susceptibility to schizophrenia.
我们和其他人先前对有多例精神分裂症患者的家族进行的连锁分析证实，11号染色体q22 - 24区域与精神分裂症的病因有关，对数优势分数分别为3.4和3.1。我们现在报告对11q22 - 24区域内一个易感基因的精细定位，该定位基于伦敦大学学院（UCL）的一个样本，其中有496例患者和488名超常对照。随后通过对一个阿伯丁样本的研究进行了验证，该样本包括858例患者和591名对照（共计2433人：1354例精神分裂症患者和1079名对照）。位于FXYD6基因内部或附近的7个微卫星或单核苷酸多态性（SNP）标记在UCL样本中显示出与精神分裂症存在经验性显著的等位基因关联（对于D11S1998，P = 0.021；对于rs3168238，P = 0.009；对于TTTC20.2，P = 0.048；对于rs1815774，P = 0.049；对于rs4938445，P = 0.010；对于rs4938446，P = 0.025；对于rs497768，P = 0.023）。还发现几种单倍型与精神分裂症有关；例如，通过全局置换检验发现，由标记rs10790212 - rs4938445 - rs497768组成的单倍型Hap - F21与精神分裂症有关（P = 0.002）。然后对UCL样本中的阳性标记在阿伯丁样本中进行基因分型。发现其中两个SNP在苏格兰样本中与精神分裂症有关（对于rs4938445，P = 0.044；对于rs497768，P = 0.037）。单倍型Hap - F21在阿伯丁样本中也显示出与精神分裂症有显著关联，且关联的等位基因相同（P = 0.013）。FXYD6基因编码一种名为“磷酸海马素”的蛋白质，该蛋白质在被认为与精神分裂症有关大脑区域中高度表达。该蛋白质通过根据组织的特定生理需求调节钠钾ATP酶的动力学特性来发挥作用。FXYD6基因或相关启动子/控制区域的病因性碱基变化可能会导致磷酸海马素功能异常或表达异常，并增加对精神分裂症的遗传易感性。
