DOI: 10.5061/dryad.zkh18938p
title: Appendix: Association between hemostatic profile and migraine: a Mendelian randomization analysis

description: 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.
description: 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.