Objective: Through the utilization of the data specifically related to early-onset ischemic stroke, we aimed to investigate the causal effects of migraine and its subtypes on the risk of early-onset ischemic stroke using the two-sample Mendelian randomization method. Methods: Genetic instrumental variables were acquired from two sources with the largest sample sizes available. Summary data for early-onset ischemic stroke was acquired from a study encompassing individuals aged 18 to 59 years, comprising 16,730 cases and 599,237 non-stroke controls. The random-effects inverse variance weighted method was used as the primary analysis approach. Results: The Mendelian randomization analysis revealed no association between overall migraine and migraine without aura with the risk of early-onset ischemic stroke. However, migraine with aura showed a suggestive association with an elevated risk of early-onset ischemic stroke, with odds ratios of 1.114 (95% confidence interval = 1.005 to 1.236, p-value = 0.040) and 1.062 (95% confidence interval = 1.002 to 1.126, p-value = 0.042) based on instruments from two independent sources. The odds ratio was 1.074 (95% confidence interval = 1.022 to 1.130, p-value = 0.005) based on instruments from both two sources. No evidence of heterogeneity or horizontal pleiotropy was found. Furthermore, a positive genetic correlation was found between migraine with aura and early-onset ischemic stroke (genetic correlation = 0.208, 95% confidence interval = 0.038 to 0.377, p-value = 0.016). By contrast, migraine with aura was not related to ischemic stroke of all adults. Conclusion: This study provides evidence of a causal relationship between migraine with aura and the risk of early-onset ischemic stroke.

The authors have declared no competing interest.

This study did not receive any funding

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Summary data for migraine by Bjornsdottir et al. were obtained from https://www.decode.com/summarydata/. Summary data for migraine by International Headache Genetics Consortium were obtained from https://www.headachegenetics.org/datasets-cohorts. Summary data for early-onset ischemic stroke were obtained from the Cerebrovascular Disease Knowledge Portal (https://cd.hugeamp.org/).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The supporting data for this study can be found in the supplementary files of the article as well as in the referenced studies within this article. Summary data for migraine by Bjornsdottir et al. were obtained from https://www.decode.com/summarydata/. Summary data for migraine by International Headache Genetics Consortium were obtained from https://www.headachegenetics.org/datasets-cohorts. Summary data for early-onset ischemic stroke were obtained from the Cerebrovascular Disease Knowledge Portal (https://cd.hugeamp.org/).

https://www.decode.com/summarydata/

https://www.headachegenetics.org/datasets-cohorts

https://cd.hugeamp.org/