Insights into modifiable risk factors of migraine: a Mendelian randomization analysis

Increasing epidemiological evidence has reported that various factors are associated with migraine risk and subtypes. Nevertheless, definitive conclusions regarding whether the putative modifiable risk factors are causally related to the pathogenesis of migraine have not been drawn. Using single-nucleotide polymorphisms as instrumental variables, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of 38 modifiable factors, including dietary nutrients, lifestyle factors, cardiometabolic diseases, and associated traits, as well as reproductive characteristics and sex hormones, on the risk of migraine, migraine with aura (MA), and migraine without aura (MO). Subsequently, meta-analyses were performed to combine causal estimates from two independent genome-wide association studies. In the combined findings with multiple test correction, genetically predicted higher alcohol intake frequency (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.12–1.40), lifetime smoking index (OR: 1.24; 95% CI: 1.08–1.42), insomnia (OR: 1.20; 95% CI: 1.17–1.24), long sleep duration (OR: 1.26; 95% CI: 1.07–1.50), and hypertension (OR: 1.76; 95% CI: 1.47–2.11) were causally linked to migraine incidence. Subgroup analyses revealed higher carbohydrate and sugar intake, alcohol consumption frequency, lifetime smoking index, insomnia, and hypertension causally increased susceptibility to MA, while later age at first birth (AFB) had a protective effect on MA risk. Meanwhile, the MR findings revealed a detrimental association between alcohol intake frequency, insomnia, hypertension, and early AFB and MO incidence. Overall, our study demonstrated various causal risk factors for migraine and its subtypes risk, providing insights into its pathogenesis and potential prevention strategies. Further research is needed to validate these findings and explore their clinical implications and underlying mechanisms.