Genetic evidence for causal association between migraine and dementia: a mendelian randomization study

Abstract

Background: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB).

Methods: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis.

Results: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings.

Conclusion: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Keywords: Alzheimer’s disease; Dementia; Dementia with Lewy bodies; Frontotemporal dementia; Mendelian randomization; Migraine; Vascular dementia.

Fig. 1

Overview of this bidirectional MR study design

Fig. 2

IVs should satisfy three core assumptions

Fig. 3

Scatter plots of the causal impact of migraine on dementia. The scatter plots show the causal effects of migraine on any dementia (A), Alzheimer’s disease (B), vascular dementia (C), frontotemporal dementia (D), dementia with lewy bodies (E), when migraine is the risk factor. Three lines reveal the estimated effect sizes by MR methods (IVW, MR-Egger and weighted median)

Fig. 4

Scatter plots of the causal impact of dementia on migraine. The scatter plots show the causal effects of any dementia (A), Alzheimer’s disease (B), vascular dementia (C), frontotemporal dementia (D), dementia with lewy bodies (E) on migraine, when five types of dementia are the risk factors. Three lines reveal the estimated effect sizes by MR methods (IVW, MR-Egger and weighted median)

Fig. 5

Leave-one-out plots of the causal impact of migraine on dementia. Leave-one-out plots show the association between any dementia (A), Alzheimer’s disease (B), vascular dementia (C), frontotemporal dementia (D), dementia with lewy bodies (E) and migraine when migraine is the risk factor, using IVs that excluded 1 SNP at a time from the overall instrumental variable or using IVW as an MR method to exclude all SNPs. Bars show effect size and 95% confidence interval

Fig. 6

Leave-one-out plots of the causal impact of dementia on migraine. Leave-one-out plots show the association between any dementia (A), Alzheimer’s disease (B), vascular dementia (C), frontotemporal dementia (D), dementia with lewy bodies (E) and migraine when 5 types of dementia are the risk factors, using IVs that excluded 1 SNP at a time from the overall instrumental variable or using IVW as an MR method to exclude all SNPS. Bars show effect size and 95% confidence interval