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Intracranial hypertension and hemorrhage progression are critical secondary injuries in severe TBI; these are mediated by the SUR1\u2010TRPM4 channel (a target in clinical trials). We aimed to deconstruct the complex network surrounding SUR1\u2010TRPM4 and define the cumulative impact of key genetic variants on mechanistically connected secondary injuries\/outcomes after severe TBI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This exploratory study analyzed 492 prospectively enrolled patients with severe TBI. A network of regulators, mediators, and effectors upstream\/downstream of SUR1\u2010TRPM4 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\u2010risk scores (PRS) were constructed and interrogated. Spatial modeling and functional predictions were determined. Single\u2010cell cortical transcriptomic differences were assessed in a parallel murine TBI model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ninety\u2010seven genes (625 SNVs) were analyzed. Nineteen genes contained variants associated with all outcomes (intracranial pressure, hemorrhage progression, and GOS score;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Twenty\u2010two genes (42 SNVs) retained significance for \u2265\u20091 outcome, with overlap across outcomes. Functions included Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2010transport\/signaling, glutamate\u2010clearance, neuroinflammation, and cell death. Single\u2010cell analyses revealed cell\u2010specific gene\u2010expression differences. SNVs were brain\u2010specific cis\u2010expression 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 (\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      , receiver operating characteristic [ROC]).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Polygenic variability in key nodes linked to SUR1\u2010TRPM4 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. 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