Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA.
Neuropsychopharmacology. 2021 Mar;46(4):763-773. doi: 10.1038/s41386-020-00900-8. Epub 2020 Nov 10.
Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and demonstrate endocrine and molecular alterations compared to controls. This study reports the association between parental Holocaust exposure and genome-wide gene expression in peripheral blood mononuclear cells (PBMC) from 77 Holocaust survivor offspring and 15 comparison subjects. Forty-two differentially expressed genes (DEGs) were identified in association with parental Holocaust exposure (FDR-adjusted p < 0.05); most of these genes were downregulated and co-expressed in a gene network related to immune cell functions. When both parental Holocaust exposure and maternal age at Holocaust exposure shared DEGs, fold changes were in the opposite direction. Similarly, fold changes of shared DEGs associated with maternal PTSD and paternal PTSD were in opposite directions, while fold changes of shared DEGs associated with both maternal and paternal Holocaust exposure or associated with both maternal and paternal age at Holocaust exposure were in the same direction. Moreover, the DEGs associated with parental Holocaust exposure were enriched for glucocorticoid-regulated genes and immune pathways with some of these genes mediating the effects of parental Holocaust exposure on C-reactive protein. The top gene across all analyses was MMP8, encoding the matrix metalloproteinase 8, which is a regulator of innate immunity. To conclude, this study identified a set of glucocorticoid and immune-related genes in association with parental Holocaust exposure with differential effects based on parental exposure-related factors.
创伤幸存者的后代比对照组更有可能患上 PTSD、情绪和焦虑障碍，并表现出内分泌和分子改变。本研究报告了父母经历大屠杀与 77 名大屠杀幸存者后代和 15 名对照受试者外周血单核细胞 (PBMC) 全基因组基因表达之间的关联。发现 42 个与父母经历大屠杀相关的差异表达基因 (DEG) (FDR 调整后的 p < 0.05)；这些基因大多数下调，并在与免疫细胞功能相关的基因网络中共同表达。当父母经历大屠杀和母亲经历大屠杀的年龄都有 DEG 时，倍数变化的方向相反。同样，与母亲 PTSD 和父亲 PTSD 相关的共享 DEG 的倍数变化方向相反，而与母亲和父亲经历大屠杀或与母亲和父亲经历大屠杀的年龄相关的共享 DEG 的倍数变化方向相同。此外，与父母经历大屠杀相关的 DEG 富集了糖皮质激素调节基因和免疫途径，其中一些基因介导了父母经历大屠杀对 C 反应蛋白的影响。所有分析中排名最高的基因是 MMP8，编码基质金属蛋白酶 8，它是先天免疫的调节剂。总之，本研究确定了一组与父母经历大屠杀相关的糖皮质激素和免疫相关基因，其影响基于父母暴露相关因素的不同。
