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

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.