Exploring synaptic pathways in traumatic brain injury: a cross-phenotype genomics approach

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 (GWAS) 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 (AD), schizophrenia (SCZ), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian Randomization (MR) 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" (p-value = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p-value = 0.0001), and "Acetylcholine binding and downstream events" pathways (p-value = 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 schizophrenia, 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 outcome. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiologic overlap with other neuropsychiatric diseases.