Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
School of Education, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
J Trauma Stress. 2020 Oct;33(5):688-698. doi: 10.1002/jts.22484. Epub 2020 Mar 26.
The hypothalamic-pituitary-adrenal (HPA) axis has been of interest in attempts to identify genetic vulnerability for posttraumatic stress disorder (PTSD). Although numerous HPA-axis genes have been implicated in candidate gene studies, the findings are mixed and interpretation is limited by study design and methodological inconsistencies. To address these inconsistencies in the PTSD candidate gene literature, we conducted meta-analyses of HPA-related genes from both a traditional single nucleotide polymorphism (SNP)-level analysis and a gene-level analysis, using novel methods aggregating markers in the same gene. Database searches (PubMed and PsycINFO) identified 24 unique articles examining six HPA-axis genes in PTSD; analyses were conducted on four genes (ADCYAP1R1, CRHR1, FKBP5, NR3C1) that met study eligibility criteria (original research, human subjects, main effect association study of selected genes, PTSD as an outcome, trauma-exposed control group) and had sufficient data and number of studies for use in meta-analysis, within 20 unique articles. Findings from SNP-level analyses indicated that two variants (rs9296158 in FKBP5 and rs258747 in NR3C1) were nominally associated with PTSD, ps = .001 and .001, respectively, following multiple testing correction. At the gene level, significant relations between PTSD and both NR3C1 and FKBP5 were detected and robust to sensitivity analyses. Although study limitations exist (e.g., varied outcomes, inability to test moderators), taken together, these results provide support for FKBP5 and NR3C1 in risk for PTSD. Overall, this work highlights the utility of meta-analyses in resolving discrepancies in the literature and the value of adopting gene-level approaches to investigate the etiology of PTSD.
下丘脑-垂体-肾上腺 (HPA) 轴一直是试图确定创伤后应激障碍 (PTSD) 遗传易感性的研究热点。尽管许多 HPA 轴基因已在候选基因研究中被涉及，但研究结果存在差异，且由于研究设计和方法学的不一致，解释受到限制。为了解决 PTSD 候选基因文献中的这些不一致性，我们对 HPA 相关基因进行了荟萃分析，包括传统的单核苷酸多态性 (SNP) 水平分析和基因水平分析，使用新方法聚合了同一基因中的标记。数据库搜索 (PubMed 和 PsycINFO) 确定了 24 篇研究 PTSD 中六个 HPA 轴基因的独特文章；对符合研究资格标准的四个基因（ADCYAP1R1、CRHR1、FKBP5、NR3C1）进行了分析（原始研究、人类受试者、选定基因的主要效应关联研究、PTSD 作为结果、创伤暴露对照组），并在 20 篇独特的文章中，有足够的数据和研究数量用于荟萃分析。SNP 水平分析的结果表明，两个变体（FKBP5 中的 rs9296158 和 NR3C1 中的 rs258747）在经过多次测试校正后，分别与 PTSD 呈名义相关，ps =.001 和.001。在基因水平上，检测到 PTSD 与 NR3C1 和 FKBP5 之间存在显著关系，并且对敏感性分析具有稳健性。尽管存在研究局限性（例如，结果不同，无法检验调节因素），但总的来说，这些结果为 FKBP5 和 NR3C1 作为 PTSD 风险因素提供了支持。总的来说，这项工作突出了荟萃分析在解决文献中的差异和采用基因水平方法研究 PTSD 病因的价值。
