Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Brain Behav Immun. 2015 May;46:96-103. doi: 10.1016/j.bbi.2015.01.002. Epub 2015 Jan 9.
Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Both genetic and environmental factors are thought to trigger PD onset. Previously, we performed a genome-wide association study (GWAS) for PD and focused on candidate SNPs with the lowest P values. However, there seemed to be a number of polymorphisms which did not reach genome-wide significance threshold due to their low allele frequencies and odds ratios, even though they were truly involved in pathogenesis. Therefore we performed pathway analyses in order to overcome the limitations of conventional single-marker analysis and identify associated SNPs with modest effects. Each pathway analysis indicated that pathways related to immunity showed the strongest association with PD (DAVID, P=2.08×10(-6); i-GSEA4GWAS, P<10(-3); ICSNPathway, P<10(-3)). Based on the results of pathway analyses and the previously performed GWAS for PD, we focused on and investigated HLA-B and HLA-DRB1 as candidate susceptibility genes for PD. We typed HLA-B and HLA-DRB1 in 744 subjects with PD and 1418 control subjects. Patients with PD were significantly more likely to carry HLA-DRB1(∗)13:02 (P=2.50×10(-4), odds ratio=1.54). Our study provided initial evidence that HLA-DRB1(∗)13:02 and genes involved in immune-related pathways are associated with PD. Future studies are necessary to confirm these results and clarify the underlying mechanisms causing PD.
惊恐障碍（PD）是一种以惊恐发作和预期焦虑为特征的焦虑障碍。遗传和环境因素都被认为是引发 PD 发病的原因。此前，我们进行了一项针对 PD 的全基因组关联研究（GWAS），并专注于具有最低 P 值的候选 SNP。然而，由于等位基因频率和优势比低，有许多多态性似乎没有达到全基因组显著阈值，尽管它们确实参与了发病机制。因此，我们进行了途径分析，以克服传统单标记分析的局限性，并确定与适度效应相关的 SNP。每条途径分析都表明，与免疫相关的途径与 PD 相关性最强（DAVID，P=2.08×10(-6)；i-GSEA4GWAS，P<10(-3)；ICSNPathway，P<10(-3)）。基于途径分析的结果和之前进行的 PD GWAS，我们关注并研究了 HLA-B 和 HLA-DRB1 作为 PD 的候选易感性基因。我们对 744 名 PD 患者和 1418 名对照者进行了 HLA-B 和 HLA-DRB1 分型。PD 患者携带 HLA-DRB1(∗)13:02 的可能性显著更高（P=2.50×10(-4)，优势比=1.54）。我们的研究提供了初步证据，表明 HLA-DRB1(∗)13:02 和与免疫相关途径相关的基因与 PD 相关。需要进一步的研究来证实这些结果并阐明导致 PD 的潜在机制。
