Comorbidity of asthma and attention deficit hyperactivity disorder in childhood: causal, shared early-life risk factors, or shared genetic liability?

Background
The positive association between childhood asthma and attention deficit hyperactivity disorder (ADHD) has not been adequately explained. We aimed to investigate whether it is causal or whether shared genetics and/or shared early-life risk factors explain the link.

Methods
We used a two-sample Mendelian randomization (MR) to test whether there is a causal relationship between asthma and ADHD. In the Avon Longitudinal Study of Parents and Children (ALSPAC), we defined doctor-diagnosed asthma, its endotypes according to atopy determined by skin-prick tests, and the risk of ADHD by using the Strengths and Difficulties Questionnaire, all at 7 years of age. We explored whether the asthma–ADHD association was attenuated when controlling for an extensive number of early-life risk factors (N = 7165). Child polygenic risk scores (PRSs) for asthma and ADHD were calculated by using published genome-wide association studies across seven P-value thresholds (<5 × 10−8 to <.5) (N = 5425–5503).

Results
We found little evidence of a causal effect between asthma and ADHD in both directions. In ALSPAC, asthma [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.10 − 1.65], particularly non-atopic asthma (OR 1.51, 95% CI 1.09 − 2.08), was associated with ADHD in crude models, while atopic asthma was not (OR 1.00, 95% CI 0.69 − 1.45). These associations were largely attenuated after adjusting for 15 shared early-life risk factors (OR 1.14, 95% CI 0.92 − 1.41 for asthma and OR 1.24, 95% CI 0.88 − 1.74 for non-atopic asthma). There was little evidence of association between asthma PRSs and ADHD at any P-value threshold. We found evidence of an association between ADHD PRSs and asthma and non-atopic asthma at most thresholds; the strongest association was at P < 5 × 10−3 (OR 1.12, 95% CI 1.04 − 1.22, P = .004) for asthma and at P < 5 × 10−2 (OR 1.18, 95% CI 1.04 − 1.34, P = .01) for non-atopic asthma.

Conclusion
The association between asthma and ADHD in childhood is unlikely to be causal and is largely explained by shared early-life risk factors, with some evidence for a shared genetic background.