Hamilton S P, Haghighi F, Heiman G A, Klein D F, Hodge S E, Fyer A J, Weissman M M, Knowles J A
Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, New York, NY 10032, USA.
Am J Med Genet. 2000 Jun 12;96(3):324-30. doi: 10.1002/1096-8628(20000612)96:3<324::aid-ajmg18>3.0.co;2-w.
Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder.
临床和动物研究表明神经递质多巴胺在焦虑状态中起作用。在人类中，一种这样的病症是惊恐障碍，其典型特征是反复出现惊恐发作并伴有预期性焦虑。家族、分离和双生子研究表明惊恐障碍的病理生理学存在遗传成分。在本研究中，我们使用三种常见的序列多态性检测了D4多巴胺受体（DRD4）和多巴胺转运体（DAT）的基因。其中两种多态性存在于DRD4中，一种是外显子1中的12个碱基对插入/缺失，另一种是外显子3中的48个碱基对重复，第三种是DAT的3'非翻译区中的40个碱基对重复。我们采用基于家族的设计，研究了70个家族中的622个人以及82个单倍型相对风险“三联体”。对受试者的多态性位点进行基因分型，并对数据进行遗传关联和连锁分析。这三种多态性中的任何一种在三联体中的等位基因频率或基因型出现情况均无显著差异。在多种显性和隐性遗传模型模拟中，未在多重家庭中观察到DRD4或DAT多态性与惊恐障碍之间存在显著连锁。然而，分别在DAT和DRD4外显子1位点观察到约为1.1和1.05的对数优势分数（LOD）。此处报告的结果几乎不支持这些多态性在惊恐障碍中的作用。
