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

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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.

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