Skip to main content
Dryad logo

Appendix: Association between hemostatic profile and migraine: a Mendelian randomization analysis

Citation

Guo, Yanjun et al. (2022), Appendix: Association between hemostatic profile and migraine: a Mendelian randomization analysis, Dryad, Dataset, https://doi.org/10.5061/dryad.zkh18938p

Abstract

Objective:  To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.

Methods:  Two-sample Mendelian randomization (MR) instrumental leveraging available genome-wide association study (GWAS) summary statistics was applied to hemostatic measures as potential 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 eight hemostatic factors and two fibrinopeptides together with two 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]/standard deviation (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, while independent effects of FVIII and VWF could not be distinguished, and FVIIII associations were potentially affected by pleiotropy at the ABO locus. Causal effects from migraine to the hemostatic measures were not supported in reverse MR.  However, MA was not included due to lack of instruments.

Conclusions: The current study supports potential causality of increased FVIII, VWF, and phosphorylated fibrinopeptide A, and decreased fibrinogen in migraine susceptibility, especially for MA, and may provide insights into the etiology underlying the relationship between hemostasis and migraine.

Methods

The latest GWAS summary-level data for migraine (included 59,674 cases and 316,078 controls) and its subtypes: MA (included 4,837 cases and 49,174 controls) and MO (included 4,833 cases and 106,834 controls) were obtained from the International Headache Genetics Consortium (IHGC) which comprised of 22 cohorts (Data available from Dryad, Appendix). GWAS summary statistics for fibrinogen levels (N=120,246) , D-dimer levels (N=21,052), FVII activity (N=20,014), FVIII activity (N=25,897), FXI levels (N=16,169), VWF levels (N=42,379), tPA levels (N=26,929), PAI-1 levels (N=19,599), aPTT (N=9,240), and PT/INR (N=2,583) were obtained from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Hemostasis Working Group. GWAS data for the concentrations of two fibrinopeptides (fibrinopeptide A or ADSGEGDFXAEGGGVR*, and phosphorylated fibrinopeptide A or ADpSGEGDFXAEGGGVR*, N=7,824) were available at http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/ (Data available from Dryad, Appendix). Participants in all studies had European ancestry, and the genotype data were imputed either to 1000 Genomes Project or HapMap2. All participants included in each of these GWASs provided informed consent.

Funding

US National Institutes of Health and US National Institute of Neurological Disorders and Stroke, Award: R21NS09296

US National Institutes of Health and US National Institute of Neurological Disorders and Stroke, Award: R21NS104398