Max Planck Institute of Psychiatry, München, Germany.
Mol Psychiatry. 2011 Jun;16(6):647-63. doi: 10.1038/mp.2010.41. Epub 2010 Apr 6.
The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.
惊恐障碍（PD）的终身患病率在全球范围内高达 4%，有大量证据表明遗传因素对 PD 的发展起作用。全基因组关联研究（GWAS）发现 TMEM132D 中的单核苷酸多态性（SNPs）与三种独立样本中的 PD 相关，在每个样本中两个 SNP 单倍型均呈相同方向相关，在合并样本中（909 例病例和 915 例对照）的 P 值为 1.2e-7。该基因中的独立 SNPs 也与受 PD 或惊恐发作影响的患者以及受单相抑郁影响的患者的焦虑症状严重程度相关。PD 的风险基因型与额皮质中 TMEM132D mRNA 表达水平升高有关。同时，使用特质焦虑极端的小鼠模型，我们还可以进一步表明，焦虑相关行为与前扣带皮层中 Tmem132d mRNA 表达呈正相关，而前扣带皮层是处理焦虑/恐惧相关刺激的核心区域，在该动物模型中，Tmem132d SNP 与 F2 小组的焦虑相关行为相关。因此，TMEM132D 可能是 PD 以及更普遍的焦虑相关行为的一个重要的新候选基因。
