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

Abstract

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. 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. 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 Ca²⁺-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 (R², receiver operating characteristic [ROC]). 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 2026;99:459-477.