Gulf War Illness (GWI) is thought to be a chronic neuroimmune disorder caused by in-theater exposure during the 1990-1991 Gulf War. There is a consensus that the illness is caused by exposure to insecticides and nerve agent toxicants. However, the heterogeneity in both development of disease and clinical outcomes strongly suggests a genetic contribution. Here, we modeled GWI in 30 BXD recombinant inbred strains with a combined treatment of corticosterone (CORT) and diisopropyl fluorophosphate (DFP). We quantified transcriptomes from 409 prefrontal cortex samples. Compared to the untreated and DFP treated controls. The combined treatment significantly activated pathways such as cytokine-cytokine receptor interaction and TNF signaling pathway. Protein-protein interaction analysis defined 6 subnetworks for CORT+DFP, with the key regulators being Cxcl1, Il6, Ccnb1, Tnf, Agt, and Itgam. We also identified 21 differentially expressed genes having significant QTLs related to CORT+DFP, but without evidence for untreated and DFP treated controls, suggesting regions of the genome specifically involved in the response to CORT+DFP. We identified Adamts9 as a potential contributor to response to CORT+DFP and found links to symptoms of GWI. Furthermore, we observed a significant effect of CORT+DFP treatment on the relative proportion of myelinating oligodendrocytes, with a QTL on Chr5. We highlight three candidates, Magi2, Sema3c, and Gnai1, based on their high expression in the brain and oligodendrocyte. In summary, our results show significant genetic effects of the CORT+DFP treatment, which mirrors gene and protein expression changes seen in GWI sufferers, providing insight into the disease and a testbed for future interventions.

中文翻译：

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海湾战争疾病小鼠模型中的全基因组转录组结构

海湾战争病 (GWI) 被认为是 1990 年至 1991 年海湾战争期间由战区暴露引起的慢性神经免疫疾病。人们一致认为，这种疾病是由接触杀虫剂和神经毒剂引起的。然而，疾病发展和临床结果的异质性强烈表明存在遗传因素。在这里，我们在 30 个 BXD 重组近交系中模拟了 GWI，并结合皮质酮 (CORT) 和氟磷酸二异丙酯 (DFP) 进行处理。我们从 409 个前额皮质样本中量化了转录组。与未经处理和 DFP 处理的对照相比。联合治疗显着激活了细胞因子-细胞因子受体相互作用和 TNF 信号通路等通路。蛋白质-蛋白质相互作用分析为 CORT+DFP 定义了 6 个子网络，关键监管机构是 Cxcl1、Il6、Ccnb1、Tnf、Agt 和 Itgam。我们还鉴定了 21 个差异表达的基因，这些基因具有与 CORT+DFP 相关的显着 QTL，但没有证据表明未处理和 DFP 处理的对照，表明基因组区域专门参与对 CORT+DFP 的反应。我们将 Adamts9 确定为响应 CORT+DFP 的潜在贡献者，并发现了与 GWI 症状的联系。此外，我们观察到 CORT+DFP 处理对有髓鞘少突胶质细胞的相对比例有显着影响，QTL 位于 Chr5 上。基于它们在大脑和少突胶质细胞中的高表达，我们重点介绍了三个候选者 Magi2、Sema3c 和 Gnai1。总之，我们的结果显示了 CORT+DFP 治疗的显着遗传效应，这反映了在 GWI 患者中看到的基因和蛋白质表达变化，