Department of Clinical Genetics, Genome Diagnostics laboratory, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Department of Child and Adolescent Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
Eur J Hum Genet. 2018 Feb;26(2):247-257. doi: 10.1038/s41431-017-0059-1. Epub 2018 Jan 23.
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that may develop after a traumatic event. Here we aimed to identify epigenetic and genetic loci associated with PTSD. We included 73 traumatized police officers with extreme phenotypes regarding symptom severity despite similar trauma history: n = 34 had PTSD and n = 39 had minimal PTSD symptoms. Epigenetic and genetic profiles were based on the Illumina HumanMethylation450 BeadChip. We searched for differentially methylated probes (DMPs) and differentially methylated regions (DMRs). For genetic associations we analyzed the CpG-SNPs present on the array. We detected no genome-wide significant DMPs and we did not replicate previously reported DMPs associated with PTSD. However, GSE analysis of the top 100 DMPs showed enrichment of three genes involved in the dopaminergic neurogenesis pathway. Furthermore, we observed a suggestive association of one relatively large DMR between patients and controls, which was located at the PAX8 gene and previously associated with other psychiatric disorders. Finally, we validated five PTSD-associated CpG-SNPs identified with the array using sanger sequencing. We subsequently replicated the association of one common SNP (rs1990322) in the CACNA1C locus with PTSD in an independent cohort of traumatized children. The CACNA1C locus was previously associated with other psychiatric disorders, but not yet with PTSD. Thus, despite the small sample size, inclusion of extreme symptom severity phenotypes in a highly homogenous traumatized cohort enabled detection of epigenetic and genetic loci associated with PTSD. Moreover, here we showed that genetically confounded 450K probes are informative for genetic association analysis.
创伤后应激障碍（PTSD）是一种使人虚弱的精神疾病，可能在创伤事件后发展。在这里，我们旨在确定与 PTSD 相关的表观遗传和遗传位点。我们纳入了 73 名遭受创伤的警察，他们在症状严重程度方面存在极端表型，尽管有相似的创伤史：n=34 患有 PTSD，n=39 患有轻度 PTSD 症状。表观遗传和遗传特征基于 Illumina HumanMethylation450 BeadChip。我们寻找差异甲基化探针（DMP）和差异甲基化区域（DMR）。对于遗传关联，我们分析了阵列上存在的 CpG-SNPs。我们没有检测到全基因组显著的 DMP，也没有复制以前报道的与 PTSD 相关的 DMP。然而，对前 100 个 DMP 的 GSE 分析显示，参与多巴胺能神经发生途径的三个基因富集。此外，我们观察到患者和对照组之间存在一个较大的 DMR 的提示性关联，该 DMR 位于 PAX8 基因内，先前与其他精神疾病有关。最后，我们使用桑格测序验证了使用阵列鉴定的五个与 PTSD 相关的 CpG-SNP。随后，我们在另一组受创伤的儿童中复制了 CACNA1C 基因座中一个常见 SNP（rs1990322）与 PTSD 的关联。CACNA1C 基因座先前与其他精神疾病有关，但与 PTSD 无关。因此，尽管样本量较小，但在高度同质的创伤队列中纳入极端症状严重程度表型，能够检测到与 PTSD 相关的表观遗传和遗传位点。此外，这里我们表明，遗传上混杂的 450K 探针对遗传关联分析是有信息的。
