Asherson P, Mant R, Holmans P, Williams J, Cardno A, Murphy K, Jones L, Collier D, McGuffin P, Owen M J
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK.
Mol Psychiatry. 1996 May;1(2):125-32.
This study follows the observation of an association between homozygosity of an Mscl polymorphism in exon 1 and schizophrenia, which gives rise to a glycine to serine substitution and may alter the functional properties of the receptor. Alternatively the polymorphism may not itself be of functional significance but may be in linkage disequilibrium with another genetic variant in the coding or regulatory regions. To examine the second possibility we have screened all six exons of DRD3 by single-stranded conformational polymorphism analysis (SSCP) in 36 cases and 36 controls. Our findings suggest that the gene is highly conserved since we found no other mutations which alter protein structure. However we did detect a 5-bp deletion in the 3' intronic sequence flanking exon 5 which occurred in 7-8% of subjects within both case and control samples. A single bp substitution (g to a) in exon 3, which does not alter an amino acid was found in one affected individual. In addition we carried out a linkage study of 24 families multiply affected with schizophrenia and a non-parametric linkage study of 90 affected sibling pairs. These studies give no support for either major or moderate gene effects on schizophrenia susceptibility. Finally we have extended our association sample and observe a non-significant excess of homozygotes for the Mscl polymorphism in the sample overall (chi 2 = 2.09, 1 d.f., P = 0.15). The excess of homozygotes is specific to males (chi 2 = 4.617, 1 d.f., P = 0.032) and not females (chi 2 = 0.243, 1 d.f., NS). When these data are added to our previous published data a highly significant excess of homozygotes is observed in males (chi 2 = 13.766, 1 d.f., P = 0.00021) but not females (chi 2 = 0.606, 1 d.f., NS). In conclusion the accumulated data suggest strongly that genetic variation at the DRD3 locus increases susceptibility of schizophrenia, at least in males. At present the Mscl polymorphism in exon 1 of the gene remains a candidate for bringing about functional change in the receptor but this has not been formally tested. Other coding region polymorphisms have not been detected but it remains possible that variation within the promoter may alter receptor function.
本研究基于一项观察结果，即外显子1中Mscl多态性的纯合性与精神分裂症之间存在关联，该多态性导致甘氨酸被丝氨酸取代，可能会改变受体的功能特性。或者，该多态性本身可能没有功能意义，但可能与编码或调控区域中的另一个基因变体处于连锁不平衡状态。为了检验第二种可能性，我们通过单链构象多态性分析（SSCP）对36例患者和36名对照的DRD3基因的所有六个外显子进行了筛查。我们的研究结果表明该基因高度保守，因为我们未发现其他改变蛋白质结构的突变。然而，我们确实在位于外显子5侧翼的3'内含子序列中检测到一个5bp的缺失，在病例组和对照组样本中，均有7-8%的受试者出现该缺失。在一名患者中发现外显子3中有一个单碱基替换（g突变为a），但未改变氨基酸。此外，我们对24个精神分裂症多发家系进行了连锁研究，并对90对患病同胞对进行了非参数连锁研究。这些研究均未支持DRD3基因对精神分裂症易感性有主要或中度的基因效应。最后，我们扩大了关联样本，发现样本总体中Mscl多态性的纯合子数量有不显著的增加（卡方检验=2.09，自由度为1，P=0.15）。纯合子数量的增加在男性中具有特异性（卡方检验=4.617，自由度为1，P=0.032），而在女性中不具有特异性（卡方检验=0.243，自由度为1，无显著性差异）。当将这些数据与我们之前发表的数据相加时，发现男性中纯合子数量有高度显著的增加（卡方检验=13.766，自由度为1，P=0.00021），而女性中则没有（卡方检验=0.606，自由度为1，无显著性差异）。总之，累积的数据强烈表明，DRD3基因座的遗传变异增加了精神分裂症的易感性，至少在男性中如此。目前，该基因外显子1中的Mscl多态性仍是导致受体功能改变的一个候选因素，但尚未经过正式验证。尚未检测到其他编码区域的多态性，但启动子区域内的变异仍有可能改变受体功能。
