Genetic susceptibility and risk of cardiometabolic diseases after traumatic brain injury

Background Traumatic brain injury (TBI) has been linked to increased long-term cardiovascular and metabolic risk, but whether this reflects an independent effect of TBI or shared inherited susceptibility remains unclear. We aimed to (1) evaluate whether TBI is independently associated with incident coronary artery disease (CAD), hypertension (HTN), type 2 diabetes (DM2), and hypercholesterolemia (HLD); (2) test interactions between TBI and polygenic risk scores (PRS) on cardiometabolic outcomes; and (3) determine whether PRS improves risk prediction among TBI survivors beyond traditional clinical factors. Methods We performed two analyses in the UK Biobank. TBI was modeled as a time-varying exposure in Cox proportional hazards models to evaluate associations with incident cardiometabolic outcomes. Among participants with TBI, outcome-specific PRS were assessed for prediction beyond clinical covariates. A composite cardiometabolic meta-PRS was externally validated in the Mass General Brigham Biobank. Results Among 487,252 UK Biobank participants, 4,309 sustained incident TBI. TBI was independently associated with higher risk of CAD, HTN, DM2, and HLD. Joint TBI–PRS effects were largely additive. PRS was independently associated with each outcome among TBI survivors, most strongly for CAD and DM2. The meta-PRS was associated with greater post-TBI cardiometabolic risk in both UK Biobank (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.09–1.29) and the external replication cohort (HR, 1.15; 95% CI, 1.03–1.29). Conclusion TBI was independently associated with higher long-term cardiometabolic risk beyond traditional risk factors. Genetic susceptibility may further refine post-TBI risk stratification.