{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:09:22Z","timestamp":1768568962618,"version":"3.49.0"},"posted":{"date-parts":[[2025,6,16]]},"group-title":"Genetic and Genomic Medicine","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries.\n                  <jats:italic>BDNF<\/jats:italic>\n                  DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain\u2019s response and help identify TBI-specific epigenetic patterns relevant to later recovery. Therefore, the purpose of this study was to examine whether\n                  <jats:italic>BDNF<\/jats:italic>\n                  DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Data were derived from the Epigenetic Effects on TBI Recovery (EETR) study, a prospective, longitudinal cohort study conducted at UPMC Children\u2019s Hospital of Pittsburgh. Children aged 3 to 18 years hospitalized at a minimum of overnight for complicated mild to severe TBI or OI without head trauma were enrolled. Exclusion criteria included prior hospitalization for TBI, pre-existing neurological or psychiatric conditions, or sensory or motor impairments precluding study participation. Blood samples were collected during hospitalization (mean=31.6 hours post-injury) and at 6 (mean=216.9 days) and 12 months (mean=405.9 days) post-injury. The primary outcome variable was DNAm assessed via pyrosequencing at five quality-controlled CpG sites in the\n                  <jats:italic>BDNF<\/jats:italic>\n                  gene (chromosome 11, hg38 positions 27722033, 27722036, 27722047, 27701612, and 27701614). The primary exposure was injury type (TBI vs. OI), with severity (measured via Glasgow Coma Scale [GCS]) examined as a secondary exposure within the TBI group. Primary covariates included age, sex, and race; secondary covariates included pubertal status, age-adjusted BMI, non-head injury severity, socioeconomic status, and psychosocial adversity. The final analysis sample included n=189 participants with TBI and n=105 participants with OI. Participants were 66.3% male, 83.2% White, and had a mean age of 10.6 (\u00b14.4) years at the time of enrollment. Acutely, children with TBI showed significantly lower DNAm at three of five sites (3.17%\u2013 5.83% lower; p=0.0044 to 6.48E-06) while controlling for age, sex, and race. One site remained significantly lower at 12 months (8.56% lower; p=0.0045); no significant differences were observed at 6 months. Observed differences remained robust across sensitivity models adjusting for secondary covariates. GCS-measured TBI severity was not associated with DNAm at any time point. These findings suggest that\n                  <jats:italic>BDNF<\/jats:italic>\n                  DNAm differs between children with TBI and those with OI, particularly in the acute period.\n                  <jats:italic>BDNF<\/jats:italic>\n                  DNAm differences may reflect early biological responses that are specific to TBI.\n                <\/jats:p>","DOI":"10.1101\/2025.06.16.25329571","type":"posted-content","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:50:23Z","timestamp":1750121423000},"source":"Crossref","is-referenced-by-count":0,"title":["Differential DNA Methylation of the Brain-Derived Neurotrophic Factor Gene is Observed after Pediatric Traumatic Brain Injury Compared to Orthopedic Injury"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7690-5485","authenticated-orcid":false,"given":"Lacey 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