{
  "abstract": "BackgroundPost-traumatic epilepsy (PTE) can be a lifelong complication of traumatic brain injury (TBI). We hypothesize that PTE develops according to a Two-Hit Hypothesis, in which the first \"hit\" is a genetic predisposition and the second \"hit\" is the TBI. Using two independent datasets, we provide the first evidence that PTE is a polygenic disorder, and we propose a whole-exome sequencing (WES) based framework to estimate the risk of developing PTE.\n\nMethodsFrom a pool of thousands of screened veterans, we recruited a cohort of PTE subjects (n=28) and a control cohort of TBI subjects without PTE (n=22) and then performed WES. Approximately 375,000 variants identified in each subject were compared to approximately 15,000 verified epilepsy-associated variants from ClinVar. Fishers exact test was used to identify variants associated with PTE, which were subsequently classified as either PTE-prone or PTE-protective. Odds ratios (ORs) were calculated at both the variant and subject levels. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive model. A second dataset was used to validate the model, and logistic calibration was performed to estimate the probability of developing PTE.\n\nResultsThirty PTE-prone and 56 PTE-protective variants were identified, with corresponding large-effect ORs. ROC analysis demonstrated excellent discrimination (AUC=0.97). Polygenic variant patterns differed between cohorts, with a predominance of PTE-prone variants in affected individuals and PTE-protective variants in controls.\n\nConclusionOur findings support a polygenic framework consistent with the Two-Hit Hypothesis. In addition, we developed a framework to estimate individual polygenic risk for PTE.",
  "abstract_shown": true,
  "affiliations": [
    "VAGLAHS"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "J. W. Chen"
    },
    {
      "name": "C. Le"
    },
    {
      "name": "K. Cui"
    },
    {
      "name": "O. M. Alexeeva"
    },
    {
      "name": "J. Joo"
    },
    {
      "name": "J. Bailey"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/am9v5qe9ntrxv.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.10.26362755",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.10.26362755v1.full",
  "id": "am9v5qe9ntrxv",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.10.26362755v1",
  "language": null,
  "licence": "CC0-1.0",
  "licence_label": "CC0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/publicdomain/zero/1.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "2738|Epilepsy research and treatment"
    ]
  ],
  "openalex": "W7212404563",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.10.26362755v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/am9v5qe9ntrxv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:27Z",
      "native_id": "10.64898/2026.09.10.26362755",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.10.26362755v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Polygenic Risk and Genetic Predisposition in Post-Traumatic Epilepsy: A Framework for Risk Estimation",
  "title_text": "Polygenic Risk and Genetic Predisposition in Post-Traumatic Epilepsy: A Framework for Risk Estimation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:27Z",
  "url": "https://research.draconitic.com/paper/am9v5qe9ntrxv",
  "venue": "medRxiv",
  "versions": []
}