Koefoed Pernille, Woldbye David P, Hansen Thomas O, Hansen Elsebeth S, Knudsen Gitte M, Bolwig Tom G, Rehfeld Jens F
Laboratory for Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark.
Psychiatr Genet. 2010 Apr;20(2):59-64. doi: 10.1097/YPG.0b013e32833511a8.
Panic disorder (PD) is a common psychiatric disease occurring more frequently in women than men. Multiple common and/or rare variants in the genome contribute to the complex etiology of the disorder. The neuropeptide cholecystokinin (CCK) and its receptors (the CCK system) have been suggested to be involved in the pathogenesis of PD.
We examined the promoter, exon, and exon-intron boundaries of the genes encoding CCK and its receptors (CCKAR and CCKBR) for variations in 187 patients with PD and 277 screened control individuals. Up to 1342 additional healthy population controls were examined for some of the variations. One CCK gene intron variation was analyzed for alternative splicing using an exon-trapping assay.
The promoter variant (-36C > T; rs1799923) and an intron 1 polymorphism (IVS1-7C > G; rs754635) in the CCK gene were found to protect against PD (P<0.05). The intron 1 variation did not seem to alter the splicing of the gene. None of the other variations found were associated with PD, but a 2-marker haplotype (rs1800855/rs1800857) in the CCKAR gene protected women against PD (P=0.004). In addition, we found two novel rare missense variations in the CCKBR gene (Lys329Asn and Pro446Leu) in two and one patient, respectively.
The results suggest that the CCK system may play a role in the pathogenesis of PD, with susceptibility alleles both protecting and contributing to the disease. Both common and rare variants seem to be involved. The involvement of the CCK system may also contribute to the increased prevalence of PD in women.
惊恐障碍（PD）是一种常见的精神疾病，女性比男性更易发病。基因组中的多个常见和/或罕见变异导致了该疾病复杂的病因。有研究表明神经肽胆囊收缩素（CCK）及其受体（CCK系统）参与了PD的发病机制。
我们检测了187例PD患者和277例筛查对照个体中编码CCK及其受体（CCKAR和CCKBR）的基因的启动子、外显子和外显子-内含子边界的变异情况。对另外1342名健康人群对照进行了部分变异检测。使用外显子捕获试验分析了一个CCK基因内含子变异的可变剪接情况。
发现CCK基因的启动子变异（-36C>T；rs1799923）和内含子1多态性（IVS1-7C>G；rs754635）可预防PD（P<0.05）。内含子1变异似乎未改变该基因的剪接。其他所发现的变异均与PD无关，但CCKAR基因中的一个双标记单倍型（rs1800855/rs1800857）可保护女性预防PD（P=0.004）。此外，我们分别在两名和一名患者中发现了CCKBR基因中的两个新的罕见错义变异（Lys329Asn和Pro446Leu）。
结果表明CCK系统可能在PD的发病机制中起作用，易感性等位基因既具有保护作用又会导致疾病发生。常见和罕见变异似乎均有涉及。CCK系统的参与可能也导致了PD在女性中患病率的增加。
