Cubells J F, van Kammen D P, Kelley M E, Anderson G M, O'Connor D T, Price L H, Malison R, Rao P A, Kobayashi K, Nagatsu T, Gelernter J
Psychiatry 116A2, VA Connecticut Health Care System, West Haven 06516, USA.
Hum Genet. 1998 May;102(5):533-40. doi: 10.1007/s004390050736.
Levels of the enzyme dopamine beta-hydroxylase (DbetaH) in the plasma and cerebrospinal fluid (CSF) are closely related biochemical phenotypes. Both are under strong genetic control. Linkage and association studies suggest the structural gene encoding DbetaH (locus name, DBH) is a major locus influencing plasma activity of DbetaH. This study examined relationships of DBH genotype determined at two polymorphic sites (a previously described GT repeat, referred to as the DBH STR and a single-base substitution at the 3' end of DBH exon 2, named DBH444 g/a), to CSF levels of DbetaH protein in European-American schizophrenic patients, and to plasma DbetaH activity in European-American patients with mood or anxiety disorders. We also investigated linkage disequilibrium (LD) between the polymorphisms in the pooled samples from those European-American subjects (n=104). Alleles of DBH444 g/a were associated with differences in mean values of CSF DbetaH levels. Alleles at both polymorphisms were associated with plasma DbetaH activity. Significant LD was observed between respective alleles with similar apparent influence on biochemical phenotype. Thus, allele A3 of the DBH STR was in positive LD with DBH444a, and both alleles were associated with lower plasma DbetaH activity. DBH STR allele A4 was in positive LD with DBH444 g, and both alleles were associated with higher plasma DbetaH activity. The results confirm that DBH is a major quantitative trait locus for plasma DbetaH activity, and provide the first direct evidence that DBH also influences CSF DbetaH levels. Both polymorphisms examined in this study appear to be in LD with one or more functional polymorphisms that mediate the influence of allelic variation at DBH on DbetaH biochemical phenotypic variation
血浆和脑脊液（CSF）中的多巴胺β-羟化酶（DβH）水平是密切相关的生化表型。二者都受强大的基因控制。连锁和关联研究表明，编码DβH的结构基因（基因座名称，DBH）是影响DβH血浆活性的主要基因座。本研究考察了在两个多态性位点（一个先前描述的GT重复序列，称为DBH STR，以及DBH外显子2 3'端的单碱基替换，命名为DBH444 g/a）确定的DBH基因型与欧美精神分裂症患者脑脊液中DβH蛋白水平以及欧美情绪或焦虑症患者血浆DβH活性之间的关系。我们还研究了来自那些欧美受试者（n = 104）的合并样本中多态性之间的连锁不平衡（LD）。DBH444 g/a的等位基因与脑脊液DβH水平的平均值差异相关。两个多态性位点的等位基因均与血浆DβH活性相关。在对生化表型有相似明显影响的各个等位基因之间观察到显著的LD。因此，DBH STR的等位基因A3与DBH444a呈正LD，且两个等位基因均与较低的血浆DβH活性相关。DBH STR等位基因A4与DBH444 g呈正LD，且两个等位基因均与较高的血浆DβH活性相关。结果证实DBH是血浆DβH活性的主要数量性状基因座，并提供了首个直接证据表明DBH也影响脑脊液DβH水平。本研究中检测的两个多态性似乎都与一个或多个功能性多态性处于LD中，这些功能性多态性介导了DBH等位基因变异对DβH生化表型变异的影响
