Identification of genes associated with susceptibility to schizophrenia

多巴胺D2受体变异体D2Cys311和野生型D2Ser311在中国人卵巢细胞中稳定表达，并通过测定细胞表面亲水性配体舒必利的结合丧失来检测多巴胺诱导的隔离。与野生型D2S受体相比，含有Cys311的D2S(多巴胺D2受体的短型亚型)受体变异体被隔离的程度明显小于野生型D2S受体，但D2L(D2受体的长型异构体)受体的隔离不如D2S受体明显，D2Ser311和D2Sys311在D2L受体上也没有明显的差异。发现两个常见的多态位点：A-584G和INS/Delg-486。死后使用G-584和不使用G-584的脑壳核中螺环酮结合的最大值没有显著差异。A-584G基因各等位基因频率在精神分裂症组和对照组之间差异无统计学意义。具有INS等位基因(p&lt；0.03)的死后脑中壳核中螺环酮结合的最大值略高于没有该等位基因的人。INS等位基因频率在发病年龄小于35岁的精神分裂症患者中显著高于对照组(p&lt；0.008)。这些结果表明，多巴胺D2受体基因的一些变异与某些类型的精神分裂症的易感性有关。

Dopamine D2 receptor variant, D2Cys311, a missense mutation changing serine 311 in the third intracellular loop to cysteine, and wild type, D2Ser311, were expressed stably in Chinese Ovary Cells and dopamine-induced sequestration was examined by measuring the loss of binding of the hydrophilic ligand sulpiride from the cell surface. A D2S (the short form isoform of dopamine D2 receptor) receptor variant containing Cys311 was found to be sequestered to a significantly smaller extent compared to wild-type D2S receptors, though sequestration of D2L (the long form isoform of D2 receptor) receptors was not so apparent as that of D2S receptors and no apparent difference was found between D2Ser311 and D2Sys311 in D2L receptors.5' flanking region of the dopamine D2 receptor gene was examined to search for nucleotide variants. Two common polymorphic sites, A-584G and Ins/DelG-486, were found. Bmax values for spiperone binding in the putamen were not significantly different between postmortem brains with G-584 and those without it. Each allele frequency of A-584G polymorphism was not significantly different between schizophrenics and controls. Bmax values for spiperone binding in the putamen were marginally significantly higher in postmortem brains with the Ins allele (p<0.03) than in those without it. The Ins allele frequency was significantly frequent in schizophrenics whose age of onset younger than 35 than in controls (p<0.008). These results suggest that some variants in the dopamine D2 receptor gene are involved in susceptibility to some types of schizophrenia.