Hettema John M, An Seon-Sook, Neale Michael C, van den Oord Edwin J C G, Kendler Kenneth S, Chen Xiangning
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298-0126, USA.
Psychiatr Genet. 2008 Apr;18(2):73-9. doi: 10.1097/YPG.0b013e3282f08a2a.
Ion channels are involved in a wide range of central nervous system functions and have been implicated in several neuropsychiatric disorders. Rodent studies suggest that the acid-sensing ion channel, ASIC1, may play a role in fear conditioning, a model for human anxiety disorders. In this study, we examined, for the first time, the human analog of ASIC1, the amiloride-sensitive cation channel 2 (ACCN2) gene, for its association with genetic risk across a range of anxiety spectrum phenotypes.
Using multivariate structural equation modeling, we selected twin pairs scoring at the extremes of a latent genetic risk factor that underlies susceptibility to neuroticism, major depression, generalized anxiety disorder, panic disorder, agoraphobia, and social phobia, from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each selected pair for whom DNA was available was entered into a 2-stage, case-control association study for the ACCN2 gene. In the resulting sample of 589 cases and 539 controls, a total of seven single nucleotide polymorphisms that represented the major allelic variation across the ACCN2 locus were screened in stage 1, the positive results of which were tested for replication in stage 2.
Although several markers or haplotypic combinations met threshold significance criteria in stage 1, their association was not replicated in stage 2. Post hoc analyses did not reveal significant association to the specific psychiatric phenotypes.
Although the ACCN2 gene may play a role in rodent fear conditioning, we could not detect association with genetic risk shared among human anxiety spectrum disorders.
离子通道参与广泛的中枢神经系统功能，并与多种神经精神疾病有关。啮齿动物研究表明，酸敏感离子通道ASIC1可能在恐惧条件反射中起作用，恐惧条件反射是人类焦虑症的一种模型。在本研究中，我们首次研究了ASIC1的人类类似物，即氨氯地平敏感阳离子通道2（ACCN2）基因，与一系列焦虑谱系表型的遗传风险之间的关联。
我们使用多变量结构方程模型，从基于人群的弗吉尼亚成人双胞胎精神病学和物质使用障碍研究中，选择了在潜在遗传风险因素极端得分的双胞胎对，该遗传风险因素是神经质、重度抑郁症、广泛性焦虑症、恐慌症、广场恐惧症和社交恐惧症易感性的基础。为每个选定的双胞胎对中可获得DNA的一名成员进行ACCN2基因的两阶段病例对照关联研究。在最终得到的589例病例和539例对照样本中，在第1阶段筛选了总共7个代表ACCN2基因座主要等位基因变异的单核苷酸多态性，其阳性结果在第2阶段进行重复测试。
尽管在第1阶段有几个标记或单倍型组合达到了阈值显著性标准，但它们的关联在第2阶段未得到重复。事后分析未发现与特定精神疾病表型有显著关联。
尽管ACCN2基因可能在啮齿动物恐惧条件反射中起作用，但我们未能检测到与人类焦虑谱系障碍共有的遗传风险之间的关联。
