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Abstract
Objective To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.
Methods Two-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests.
Results There were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, p = 6.08 × 10−05), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, p = 2.25 × 10−06), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, p = 5.44 × 10−06) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, p = 2.32 × 10−03) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the ABO locus. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments.
Conclusions The findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.
Glossary
- aPTT=
- activated partial thromboplastin time;
- FVII=
- coagulation factor VII;
- FVIII=
- coagulation factor VIII;
- FXI=
- coagulation factor XI;
- GSMR=
- generalized summary data–based Mendelian randomization;
- GWAS=
- genome-wide association study;
- HEIDI=
- heterogeneity in dependent instruments;
- IVW=
- inverse variance–weighted;
- MA=
- migraine with aura;
- MO=
- migraine without aura;
- MR=
- Mendelian randomization;
- MR-PRESSO=
- Mendelian randomization pleiotropy residual sum and outlier test;
- OR=
- odds ratio;
- PAI-1=
- plasminogen activator inhibitor-1;
- PT/INR=
- prothrombin time/international normalized ratio;
- SNP=
- single nucleotide polymorphism;
- tPA=
- tissue plasminogen activator;
- vWF=
- von Willebrand factor
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
CME Course: NPub.org/cmelist
- Received August 27, 2020.
- Accepted in final form February 24, 2021.
- © 2021 American Academy of Neurology
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