16 Feb 2022

Wimberley T et al. J Clin Psychiatry 2022; 83: 21m14033

Despite ADHD being associated with an increased injury risk, it is unknown whether early-life injuries are early manifestations of ADHD, and possibly linked to ADHD genetics in the general population. This study used a large Danish population-based cohort to estimate phenotypic and familial association between early-life injuries* and ADHD, and the genetic contribution to this association.

Data from five Danish databases of children born in Denmark between 1995–2010 and living in Denmark at age five were used in this study. Children diagnosed with ADHD or with filled prescriptions of ADHD medication, traumatic brain injury (TBI) or disease of the nervous system before age five were excluded. Genetic analyses were conducted in a sub-cohort of individuals (n=16,580) with and without ADHD, born between 1995–2005, who had genetic data available.

A total of 786,543 children were included in the study. Injury before the age of five years was sustained by 11.8% (n=92,691) of individuals, and 2.9% (n=23,107) of individuals were diagnosed with ADHD after age five and during follow-up. Sustaining an injury before age five was associated with a subsequent diagnosis of ADHD (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.55–1.66) and increasing number of injuries was associated with an increased risk of ADHD; children with ≥3 injuries were 2.5-times more likely to be diagnosed with ADHD compared with children with no injuries (HR 2.48, 95% CI 2.27–2.72). No significant relationship was found between the presence of injuries and sex (p=0.455).

By age 15, >90% of children in this study were not diagnosed with ADHD, even in children with the most injuries. The estimated risk of ADHD at age 15 ranged between 3.05% (95% CI 3.00–3.10) in children with no injuries and 8.43% (95% CI 7.64–9.22) in children with ≥3 injuries. Similar patterns were observed in both sexes, ADHD subtypes and across strata of parental education in this age group. Furthermore, male sex and the combined ADHD subtype were both associated with a higher absolute risk of ADHD. An association between ADHD and injuries in first-degree relatives was also found (mothers: HR 1.47, 95% CI 1.32–1.64; fathers: HR 1.45, 95% CI 1.33–1.57; siblings: HR 1.39, 95% CI 1.33–1.46); children with siblings who sustained an average of >2 injuries were at an increased risk of ADHD compared with those with siblings with no injuries (HR 1.81, 95% CI 1.54–2.14). Similar sex-dependent trends were observed.

The genetic analysis revealed that a higher polygenic risk score (PRS) for ADHD was associated with a higher number of injuries before age five (incidence rate ratio 1.06, 95% CI 1.00–1.14) with similar findings observed when analysed by sex. In unrelated individuals (n=14,333), moderate single-nucleotide polymorphism (SNP)-based heritability was found for ADHD and low SNP-based heritability was found for early-life injuries; a genetic correlation between ADHD and early-life injuries was strongly suggested (rg=0.53, 95% CI 0.21–0.85).

This study was limited by the fact that potential effects of other mental disorders often comorbid with ADHD on the association between early-life injuries and ADHD were not estimated. TBI was excluded from this analysis, therefore a direct causal relationship between early-life injuries and ADHD was not hypothesised. The analyses were not adjusted for parental socioeconomic status or parental behaviour, and the impact of home environment, parental behaviour or parent–child interactions were not assessed; therefore, the genetic and non-genetic contributions to the observed associations were not fully revealed. Furthermore, the data used in this study were obtained retrospectively from national health registries on clinical diagnoses of ADHD from hospital departments. It was also noted by the authors that the SNP-based heritability values may be underestimated and should be interpreted with caution due to the software used to obtain PRS. Furthermore, because ADHD was not diagnosed in >90% of cases, even in children with the most injuries, the predictive value of early-life injuries for ADHD was low. Subsequently, the authors acknowledged that these results do not provide evidence that obtaining early-life injury information at clinical assessment for ADHD should be recommended.

The authors concluded that early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD and may be an early manifestation of impairment and risks related to the disorder. It was also noted that, despite a low positive predictive value and the fact that the impact of parental behaviour was not assessed, the results suggest that the observed association between early-life injuries and ADHD may be partly explained by genetics.

Read more about early-life injuries and ADHD here

 

*Early-life injuries were defined in cohort members and their siblings as hospital-treated injury before the age of five years

Disclaimer: The views expressed here are the views of the author(s) and not those of Takeda.

Wimberley T, Brikell I, Pedersen EM, et al. Early-life injuries and the development of attention-deficit/hyperactivity disorder. J Clin Psychiatry 2022; 83: 21m14033.

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