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May 18, 2021; 96 (20) Article

Association Between Hemostatic Profile and Migraine

A Mendelian Randomization Analysis

Yanjun Guo, View ORCID ProfilePamela M. Rist, View ORCID ProfileMaria Sabater-Lleal, View ORCID ProfilePaul de Vries, Nicholas Smith, View ORCID ProfilePaul M Ridker, View ORCID ProfileTobias Kurth, View ORCID ProfileDaniel I. Chasman
First published April 1, 2021, DOI: https://doi.org/10.1212/WNL.0000000000011931
Yanjun Guo
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
MD, PhD
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Pamela M. Rist
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Maria Sabater-Lleal
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Paul de Vries
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Nicholas Smith
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Paul M Ridker
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Tobias Kurth
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Daniel I. Chasman
From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.
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Citation
Association Between Hemostatic Profile and Migraine
A Mendelian Randomization Analysis
Yanjun Guo, Pamela M. Rist, Maria Sabater-Lleal, Paul de Vries, Nicholas Smith, Paul M Ridker, Tobias Kurth, Daniel I. Chasman
Neurology May 2021, 96 (20) e2481-e2487; DOI: 10.1212/WNL.0000000000011931

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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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Letters: Rapid online correspondence

  • Reader Response: Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis
    • Khichar Shubhakaran, Senior Professor Neurology, MDM Hospital, Dr. S.N Medical College, Jodhpur(Rajasthan), India-342003
    Submitted May 05, 2021
  • Reader Response: Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis
    • VINOD K GUPTA, Physician-Medical Director, GUPTA MEDICAL CENTRE, MIGRAINE-HEADACHE INSTITUTE, Greater Kailash-Part Two, New Delhi, INDIA
    Submitted April 23, 2021
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