Early-Life Injuries and the Development of Attention-Deficit/Hyperactivity Disorder

Objective: To estimate phenotypic and familial association between early-life injuries and attention- deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses. Methods: Children born in Denmark between 1995-2010 (n = 786,543) were followed from age 5 years until a median age of 14 years (interquartile range: 10-18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward-treated injuries by age 5. In a subset of ADHD cases and controls born 1995 to 2005 who had genetic data available (n = 16,580), we estimated incidence rate ratios (IRRs) for the association between PRS-ADHD and number of injuries before age 5 and the genetic correlation between ADHD and any injury before age 5. Results: Injuries were associated with ADHD (HR = 1.61; 95% CI, 1.55-1.66) in males (HR = 1.59; 1.53-1.65) and females (HR = 1.65; 1.54-1.77), with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs 3.1% (no injuries). ADHD was also associated with injuries in relatives, with a stronger association in first- than second-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population (IRR = 1.06; 1.00-1.14), with a genetic correlation of 0.53 (0.21-0.85). Conclusions: Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behavior remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD.