Macciardi F, Petronis A, Van Tol H H, Marino C, Cavallini M C, Smeraldi E, Kennedy J L
Istituto Scientifico H San Raffaele, Department of Neuroscience, University of Milano, School of Medicine.
Arch Gen Psychiatry. 1994 Apr;51(4):288-93. doi: 10.1001/archpsyc.1994.03950040032004.
Among the different dopamine receptors, the D4 dopamine receptor is of particular interest in schizophrenia because of its high affinity for the atypical neuroleptic clozapine. Recently, the gene for the D4 dopamine receptor has been cloned and a new and intriguing polymorphism has been described. Different versions of the receptor have varying affinity for clozapine, and thus variant froms of D4 with differing pharmacologic activity exist in the human population. Our hypothesis was that these variants play a role in susceptibility to psychotic illness. Thus, our objective was to test the D4 dopamine receptor genes for linkage to schizophrenia.
Our genetic linkage study was carried out in a large Italian kindred segregating schizophrenia. Diagnoses were made by using a structured clinical interview and a consensus diagnosis was established. For the computer analysis, 80 members of the family were constructed into a linked set of relatives with 15 of these individuals affected by schizophrenia. The functional variants of the D4 dopamine receptor gene were identified by a combination of Southern blot techniques and the polymerase chain reaction. The gene for tyrosine hydroxylase (TH) was also tested for linkage to schizophrenia in this family. Linkage analyses were done with both a single-locus and a two-locus model.
Our results revealed significantly negative lod scores in the region of the D4 dopamine receptor gene and the TH gene. The application of different models of transmission for schizophrenia had an effect on the magnitude of the lod scores, but did not modify the direction of the results.
Our results provide significant evidence for exclusion for linkage between schizophrenia and the dopamine D4 receptor gene and the TH gene under the models specified. Furthermore, we tabulated the distribution of D4 dopamine gene variants in the diseased vs healthy individuals in the family and the results showed that no specific form of the receptor gene is significantly associated with the presence of schizophrenia in the family. Our study does not exclude the possibility that regulatory elements of the D4 dopamine gene located elsewhere in the genome may be involved in the etiology of schizophrenia.
在不同的多巴胺受体中，D4多巴胺受体因对非典型抗精神病药物氯氮平具有高亲和力而在精神分裂症研究中备受关注。最近，D4多巴胺受体基因已被克隆，并发现了一种新的有趣的多态性。受体的不同版本对氯氮平的亲和力各异，因此人群中存在具有不同药理活性的D4变体。我们的假设是这些变体在精神病性疾病易感性中起作用。因此，我们的目标是检测D4多巴胺受体基因与精神分裂症的连锁关系。
我们的基因连锁研究在一个患有精神分裂症的意大利大家族中进行。诊断采用结构化临床访谈，并建立了共识诊断。为进行计算机分析，该家族的80名成员被构建成一组有亲缘关系的群体，其中15人患有精神分裂症。通过Southern印迹技术和聚合酶链反应相结合的方法鉴定D4多巴胺受体基因的功能变体。该家族中酪氨酸羟化酶（TH）基因也被检测与精神分裂症的连锁关系。采用单基因座和双基因座模型进行连锁分析。
我们的结果显示在D4多巴胺受体基因和TH基因区域的对数优势比得分显著为负。应用不同的精神分裂症传递模型对对数优势比得分的大小有影响，但未改变结果的方向。
我们的结果提供了重要证据，在指定模型下排除精神分裂症与多巴胺D4受体基因和TH基因之间的连锁关系。此外，我们列出了家族中患病个体与健康个体中D4多巴胺基因变体的分布情况，结果表明受体基因的任何特定形式与家族中精神分裂症的存在均无显著关联。我们的研究并不排除基因组中其他位置的D4多巴胺基因调控元件可能参与精神分裂症病因的可能性。
