Genetic liability to ADHD and migraine risk: Mendelian randomization evidence for behavioural and psychiatric pathways

Background: Attention-deficit/hyperactivity disorder (ADHD) and migraine frequently co-occur, but the mechanisms underlying this association remain unclear. Examining migraine with aura and without aura separately may help clarify whether ADHD-related pathways are shared across migraine subtypes or differ by aura status. Methods: Two-sample Mendelian randomization (MR) was used to examine the effect of genetic liability to ADHD on overall migraine and on migraine subtypes defined by aura status. MR-based mediation was then used to assess whether behavioural, psychiatric, sleep-related, education, and cardiometabolic traits contribute to these effects. Results: MR provided evidence for an effect of ADHD genetic liability on overall migraine risk (OR = 1.48, 95% CI =1.2, 1.82), with similar effect sizes for migraine with aura (MA) (OR=1.52, 95% CI = 1.18, 1.96) and migraine without aura (MO) (OR = 1.65, 95% CI = 1.19, 2.31). Depression, alcohol intake frequency, lifetime smoking index, ever smoke, risk taking behaviours, insomnia, and college education showed evidence for partial mediation, explaining approximately 34.17% (95% CI = 6.17%, 61.63%), 14.44% (95% CI = 0%, 28.87%), 37.25% (95% CI = 11.86%, 63.64%), and 29.24% (95% CI = 6.12%, 52.37%) of the total effect, individually. Subtype analyses suggested broadly similar patterns across MA and MO, with no clear subtype-specific differences. Conclusion: Our findings provide evidence that ADHD common variant genetic liability increases migraine risk, including both MA and MO. The association appears unlikely to be explained by a single pathway and may involve the contribution of depression-related, lifestyle-related, and education-related processes.