Polygenic Vulnerability to Intracranial Hypertension, Hemorrhage Progression, and Outcome in Traumatic Brain Injury

Authors

• Margaux E. Miller, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Benjamin E. Zusman, Department of Neurology, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
• Chia-Ling Phuah, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Erin McNally, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• David O. Okonkwo, Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
• Matthew Pease, Department of Neurological Surgery, School of Medicine, Indiana University, Bloomington, IN.
• Shashvat M. Desai, HonorHealth Research Institute, Scottsdale, AZ.
• Anupama Rani, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Nasathapot Namphol, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Aditya Kumar, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Raemier A. Javelosa, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Adam T. Eberle, Departments of Neurological Surgery, Barrow Neurological Institute, Phoenix, AZ.
• Semeon Afework, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.
• Joshua Catapano, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA.
• Charles S. Cox, Department of Neurosciences, McGovern Medical School, University of Texas, Houston, TX.
• Patrick M. Kochanek, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
• Yvette P. Conley, School of Nursing, University of Pittsburgh, Pittsburgh, PA.
• Ava M. Puccio, Department of Neurological Surgery, School of Medicine, Indiana University, Bloomington, IN.
• Ruchira M. Jha, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ.

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