{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T20:44:47Z","timestamp":1777927487612,"version":"3.51.4"},"reference-count":85,"publisher":"SAGE Publications","issue":"1-2","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurotrauma"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    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\u2019s 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: \u201cSerotonin clearance from the synaptic cleft\u201d (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    = 0.0001), \u201cPresynaptic nicotinic acetylcholine receptors\u201d (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    = 0.0003), \u201cPostsynaptic nicotinic acetylcholine receptors\u201d (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    = 0.0003), \u201cHighly sodium permeable postsynaptic acetylcholine nicotinic receptors\u201d (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    = 0.0001), and \u201cAcetylcholine binding and downstream events\u201d pathways (\n                    <jats:italic toggle=\"yes\">p<\/jats:italic>\n                    = 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.\n                  <\/jats:p>","DOI":"10.1089\/neu.2024.0153","type":"journal-article","created":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T13:18:00Z","timestamp":1726147080000},"page":"131-142","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring Synaptic Pathways in Traumatic Brain Injury: A Cross-Phenotype Genomics Approach"],"prefix":"10.1177","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7415-2566","authenticated-orcid":false,"given":"Savvina","family":"Prapiadou","sequence":"first","affiliation":[{"name":"University of Patras Medical School, Patras, Greece."},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernst","family":"Mayerhofer","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marios K.","family":"Georgakis","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mart","family":"Kals","sequence":"additional","affiliation":[{"name":"Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farid","family":"Radmanesh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Division of Neurocritical Care, Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saef","family":"Izzy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvia","family":"Richardson","sequence":"additional","affiliation":[{"name":"MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Okonkwo","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ava","family":"Puccio","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Temkin","sequence":"additional","affiliation":[{"name":"Departments of Neurological Surgery and Biostatistics, University of Washington, Seattle, Washington, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aarno","family":"Palotie","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuli","family":"Ripatti","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland."},{"name":"Department of Public Health, University of Helsinki, Helsinki, Finland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramon","family":"Diaz-Arrastia","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murray B.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine, and School of Public Health, University of California, La Jolla, California, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoff","family":"Manley","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of California, San Francisco, California, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David K.","family":"Menon","sequence":"additional","affiliation":[{"name":"Division of Anaesthesia, University of Cambridge, Cambridge, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Rosand","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livia","family":"Parodi","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher D.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of The Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies)","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.3171\/2017.10.JNS17352"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000933"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2013.22"},{"key":"e_1_3_6_5_2","unstructured":"WHO.. 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