Prapiadou Savvina, Mayerhofer Ernst, Georgakis Marios K, Kals Mart, Radmanesh Farid, Izzy Saef, Richardson Sylvia, Okonkwo David, Puccio Ava, Temkin Nancy, Palotie Aarno, Ripatti Samuli, Diaz-Arrastia Ramon, Stein Murray B, Manley Geoff, Menon David K, Rosand Jonathan, Parodi Livia, Anderson Christopher D
University of Patras Medical School, Patras, Greece.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
J Neurotrauma. 2025 Jan;42(1-2):131-142. doi: 10.1089/neu.2024.0153. Epub 2024 Oct 7.
Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from genome-wide association studies with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease, schizophrenia (SCZ), major depressive disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and autism spectrum disorder. Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian randomization to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" ( = 0.0001), "Presynaptic nicotinic acetylcholine receptors" ( = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" ( = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" ( = 0.0001), and "Acetylcholine binding and downstream events" pathways ( = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and SCZ, suggesting possible pathophysiologic commonalities. In this study, we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcomes. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiological overlap with other neuropsychiatric diseases.
创伤性脑损伤（TBI）是全球导致死亡和残疾的主要原因之一，目前缺乏有效的治疗方法来促进恢复。突触重塑被认为是影响TBI后恢复结果的一种机制。我们试图使用通路富集工具和全基因组基因型数据，研究影响突触维持的常见机制在TBI和其他神经精神疾病之间是否存在共性，目的是找出新的治疗靶点。我们采用了一种综合方法，将全基因组关联研究的数据与通路和基因集富集分析相结合。基于文献综述和Reactome数据库驱动的方法相结合，以识别与TBI恢复结果相关的突触相关通路，并评估与涉及突触相关病理生物学机制的疾病（包括阿尔茨海默病、精神分裂症（SCZ）、重度抑郁症、创伤后应激障碍、注意力缺陷多动障碍和自闭症谱系障碍）的共同关联。使用MAGMA及其扩展程序e - 和H - MAGMA进行基因和通路水平的富集分析，随后进行孟德尔随机化以研究潜在的因果关联。在所测试的98条通路中，有32条在纳入的疾病中显著富集。在TBI恢复结果方面，我们在五条通路中发现显著富集：“突触间隙中血清素的清除”（P = 0.0001）、“突触前烟碱型乙酰胆碱受体”（P = 0.0003）、“突触后烟碱型乙酰胆碱受体”（P = 0.0003）、“高钠通透性突触后乙酰胆碱烟碱型受体”（P = 0.0001）以及“乙酰胆碱结合及下游事件”通路（P = 0.0003）。这些关联突出了胆碱能和血清素能系统在TBI后恢复中的潜在作用。其中三条通路在TBI和SCZ之间存在共性，表明可能存在病理生理共性。在本研究中，我们利用跨脑疾病的比较和综合基因组方法，这些疾病共享突触机制，以探索TBI恢复结果的病理生理学。我们的结果表明TBI恢复结果与突触通路之间存在关联，以及与其他神经精神疾病存在病理生物学重叠。
