Mendelian randomization analysis reveals causal effects of migraine and its subtypes on early-onset ischemic stroke risk

Abstract

Previous observational studies have suggested at a potential link between migraine, particularly migraine with aura, and the susceptibility to early-onset ischemic stroke. We aimed to investigate the causal effects of genetically determined migraine and its subtypes on the risk of early-onset ischemic stroke using the two-sample Mendelian randomization method. Genetic instrumental variables associated with migraine and its subtypes 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 18-59 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. Additionally, linkage disequilibrium score regression analysis was used to evaluate the genetic correlation. 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. By contrast, migraine with aura was not related to ischemic stroke in all adults. Furthermore, a significant 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). This study provides evidence of a causal relationship between migraine with aura and the risk of early-onset ischemic stroke, as well as a positive genetic correlation between them.

Keywords: Causality; Genetic correlation; Ischemic stroke; Mendelian randomization; Migraine.

Fig. 1

Design of two-sample Mendelian randomization in the present study. In MR study, three key assumptions are crucial: the relevance assumption, stating that the genetic variant strongly associates with the exposure; the independence assumption, ensuring the genetic variant’s independence from confounders; and the exclusion restriction assumption, which dictates that the genetic variant solely affects the outcome through the exposure factor. For instrumental SNPs used in both data sources, we first combined un-clumped SNPs from the two sources and then conducted the clumping procedure. Abbreviations: Any, any migraine; MA, migraine with aura; MO, migraine without aura; SNP, single nucleotide polymorphism; IHGC, International Headache Genetics Consortium.

Fig. 2

Inverse variance weighted estimates of migraine on risk of early-onset ischemic stroke. Het_p indicates p-value of heterogeneity test. Ple_p indicates p-value of pleiotropy test. Abbreviations: SNP, single nucleotide polymorphism; IHGC, International Headache Genetics Consortium; OR, odds ratio; CI, confidence interval.

Fig. 3

Scatter plots of SNP effect on migraine with aura and SNP effect on early-onset ischemic stroke. (A) instrumental SNPs based on study by Bjornsdottir et al. 2023; (B) instrumental SNPs based on study by IHGC; C: instrumental SNPs based on both two sources. Abbreviations: SNP, single nucleotide polymorphism; IHGC, International Headache Genetics Consortium.

Fig. 4

Sensitivity analyses of migraine with aura on early-onset ischemic stroke. (A) Sensitivity analysis was conducted by exclusively relying on SNPs that exhibited low evidence of heterogeneity across different stroke cohorts (with I2 less than 50% and a p-value of the Q statistic greater than 0.05). (B) Sensitivity analysis was conducted using SNPs, without consideration of whether they were associated with potential confounders. Het_p indicates p-value of heterogeneity test. Ple_p indicates p-value of pleiotropy test. Abbreviations: SNP, single nucleotide polymorphism; IHGC, International Headache Genetics Consortium; OR, odds ratio; CI, confidence interval; MA, migraine with aura.

Fig. 5

Genetic correlations between migraine and ischemic stroke. Abbreviations: CI, confidence interval; MA, migraine with aura; MO, migraine without aura.