Polygenic Vulnerability to Intracranial Hypertension, Hemorrhage Progression, and Outcome in Traumatic Brain Injury
Document Type
Article
Abstract
OBJECTIVE: Growing evidence underscores the importance of host-response/secondary-injury-likely influenced by genetics-in outcome variability post-traumatic brain injury (TBI). Intracranial hypertension and hemorrhage progression are critical secondary injuries in severe TBI; these are mediated by the SUR1-TRPM4 channel (a target in clinical trials). We aimed to deconstruct the complex network surrounding SUR1-TRPM4 and define the cumulative impact of key genetic variants on mechanistically connected secondary injuries/outcomes after severe TBI. METHODS: This exploratory study analyzed 492 prospectively enrolled patients with severe TBI. A network of regulators, mediators, and effectors upstream/downstream of SUR1-TRPM4 was bioinformatically constructed. Single nucleotide variants (SNVs) were evaluated for multivariable model association with intracranial pressure, intraparenchymal hemorrhage progression, and Glasgow Outcome Scale (GOS) score. Weighted/unweighted polygenic-risk scores (PRS) were constructed and interrogated. Spatial modeling and functional predictions were determined. Single-cell cortical transcriptomic differences were assessed in a parallel murine TBI model. RESULTS: Ninety-seven genes (625 SNVs) were analyzed. Nineteen genes contained variants associated with all outcomes (intracranial pressure, hemorrhage progression, and GOS score; p < 0.05). Twenty-two genes (42 SNVs) retained significance for ≥ 1 outcome, with overlap across outcomes. Functions included Ca-transport/signaling, glutamate-clearance, neuroinflammation, and cell death. Single-cell analyses revealed cell-specific gene-expression differences. SNVs were brain-specific cis-expression quantitative trait locus (eQTLs)/missense/frameshift mutations suggesting high likelihood of biological impact. PRSs were associated with all outcomes with large effects, and markedly improved model explanatory power/performance (R, receiver operating characteristic [ROC]). INTERPRETATION: Polygenic variability in key nodes linked to SUR1-TRPM4 were associated with mechanistically related secondary injuries and outcome after severe TBI; findings suggest a major role of heritability. Functional implications indicate biological plausibility and identify novel targets. The data, whereas requiring validation, support a shift toward incorporating biologically relevant genetics in advancing precision medicine. ANN NEUROL 2025.
Publication Date
11-14-2025
Publication Title
Annals of neurology
E-ISSN
1531-8249
PubMed ID
41235589
Digital Object Identifier (DOI)
10.1002/ana.78064
Recommended Citation
Miller, Margaux E.; Zusman, Benjamin E.; Phuah, Chia-Ling; McNally, Erin; Okonkwo, David O.; Pease, Matthew; Desai, Shashvat M.; Rani, Anupama; Namphol, Nasathapot; Kumar, Aditya; Javelosa, Raemier A.; Eberle, Adam T.; Afework, Semeon; Catapano, Joshua; Cox, Charles S.; Kochanek, Patrick M.; Conley, Yvette P.; Puccio, Ava M.; and Jha, Ruchira M., "Polygenic Vulnerability to Intracranial Hypertension, Hemorrhage Progression, and Outcome in Traumatic Brain Injury" (2025). Neurology. 2047.
https://scholar.barrowneuro.org/neurology/2047