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Reappraisal of Sex Differences in Migraine

26 Pages Posted: 10 Feb 2022

See all articles by Mona Ameri Chalmer

Mona Ameri Chalmer

University of Copenhagen - Department of Neurology

Ida Callesen

University of Copenhagen - Department of Neurology

Lisette J.A. Kogelman

University of Copenhagen - Department of Neurology

Charlotte Grønvold Christensen

University of Copenhagen - Department of Neurology

Tanya Ramdal Techlo

University of Copenhagen - Department of Neurology

Peter L. Møller

Aarhus University - Department of Biomedicine

Olafur B. Davidsson

University of Copenhagen - Department of Neurology

Isa A. Olofsson

University of Copenhagen - Department of Neurology

Michael Schwinn

University of Copenhagen - Department of Clinical Immunology

Susan Mikkelsen

Aarhus University - Department of Clinical Immunology

Khoa Manh Dinh

Aarhus University - Department of Clinical Immunology

Kaspar Nielsen

Aalborg University Hospital - Department of Clinical Immunology

Mie Topholm

Odense University Hospital - Department of Clinical Immunology

Christian Erikstrup

Aarhus University - Department of Clinical Immunology

Sisse Rye Ostrowski

University of Copenhagen - Department of Clinical Medicine

Ole Birger Pedersen

Zealand University Hospital - Department of Clinical Immunology

Henrik Hjalgrim

Statens Serum Institut - Department of Epidemiology Research

Karina Banasik

Copenhagen University - Novo Nordic Foundation Center for Protein Research

Kristoffer S. Burgdorf

Copenhagen University - Novo Nordic Foundation Center for Protein Research

Mette Nyegaard

Aalborg University Hospital - Department of Clinical Immunology

Jes Olesen

University of Copenhagen - Department of Neurology

Thomas Folkmann Hansen

University of Copenhagen - Department of Neurology

More...

Abstract

Background: Migraine is the second leading cause of disability worldwide and affects two to three times more females than males. Other differences between sexes are, however, not well-documented. The aim of the present study was to assess differences between sexes in the clinical burden of migraine, i.e. attack frequency, severity, and number of non-headache symptoms, i.e. accompanying symptoms, and to assess if sex-specific genetic risk factors provide early insight into such differences.

Methods: A population-based study of 62,672 Danes. All participants completed a 105-item diagnostic migraine questionnaire, of whom 12,658 had migraine. The questionnaire had a positive predictive value of 97% for any migraine. Participants were genotyped using a genome-wide array and imputation was done using a Danish reference genome. Results were replicated in a large clinical material.

Findings: The age-related prevalence showed a marked increase during childbearing age for migraine without aura. Females also had a higher headache frequency, longer duration of migraine attacks, greater intensity of pain, more unilateral and pulsatile pain, exacerbation by physical activity, nausea, vomiting, photophobia, phonophobia, osmophobia, and allodynia than males. Females had lower effect of over-the-counter analgesics than males. We found five genome-wide significant loci for females, of which FHL5/UFL1 replicated in females with migraine (OR=1.27, 95%CI [1.12-1.45], P<0.001) and STAT6/LRP1 replicated in females with migraine without aura (OR=1.33, 95%CI [1.08-1.14], P<0.001). Secondary analyses showed a pathway enrichment of nerve growth factor signaling in females with migraine without aura (P<0.001) and glucose metabolism in males with migraine with aura (P<0.001).

Interpretation: The clinical burden of migraine in females was considerably more severe than reflected by prevalence only. Genetic findings gave early insight into the sex-specific mechanisms of migraine. The significantly higher severity of migraine in females demands increased focus on sex-specific mechanisms and treatment.Funding Candys Foundation and The Research Funding Pool at Rigshospitalet.

Funding Information: The study was financed by a grant from Candys Foundation, the CEHEAD program (J.O.) and The Research Funding Pool at Rigshospitalet (M.A.C.).

Declaration of Interests: The authors have no potential conflicts of interest with respect to the research, authorship, and/or publication of this study.

Ethics Approval Statement: Written informed consent was obtained from all participants. The DBDS study is an on-going, national study and was approved by the Danish Ethical Standards Committees in the relevant regions of Denmark (DESC) (1-10-72-95-13, SJ-740, 1-90-09-88 and 1-70-04-07) and the Danish Data Protection Agency (DDPA) (P-2019-99). Studies from the Danish Headache Center were approved by the DESC (H-2-2010-122) and the DDPA (01080/GLO-2010-10).

Keywords: Migraine, Genetics, sex differences, sex-stratification

Suggested Citation

Chalmer, Mona Ameri and Callesen, Ida and Kogelman, Lisette J.A. and Christensen, Charlotte Grønvold and Techlo, Tanya Ramdal and Møller, Peter L. and Davidsson, Olafur B. and Olofsson, Isa A. and Schwinn, Michael and Mikkelsen, Susan and Dinh, Khoa Manh and Nielsen, Kaspar and Topholm, Mie and Erikstrup, Christian and Ostrowski, Sisse Rye and Pedersen, Ole Birger and Hjalgrim, Henrik and Banasik, Karina and Burgdorf, Kristoffer S. and Nyegaard, Mette and Olesen, Jes and Hansen, Thomas Folkmann, Reappraisal of Sex Differences in Migraine. Available at SSRN: https://ssrn.com/abstract=4031580 or http://dx.doi.org/10.2139/ssrn.4031580

Mona Ameri Chalmer (Contact Author)

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Ida Callesen

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Lisette J.A. Kogelman

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Charlotte Grønvold Christensen

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Tanya Ramdal Techlo

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Peter L. Møller

Aarhus University - Department of Biomedicine ( email )

Aarhus
Denmark

Olafur B. Davidsson

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Isa A. Olofsson

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Michael Schwinn

University of Copenhagen - Department of Clinical Immunology ( email )

Susan Mikkelsen

Aarhus University - Department of Clinical Immunology ( email )

Aarhus
Denmark

Khoa Manh Dinh

Aarhus University - Department of Clinical Immunology ( email )

Aarhus
Denmark

Kaspar Nielsen

Aalborg University Hospital - Department of Clinical Immunology ( email )

Aalborg
Denmark

Mie Topholm

Odense University Hospital - Department of Clinical Immunology ( email )

Odense
Denmark

Christian Erikstrup

Aarhus University - Department of Clinical Immunology ( email )

Aarhus
Denmark

Sisse Rye Ostrowski

University of Copenhagen - Department of Clinical Medicine ( email )

Nørregade 10
Copenhagen, København DK-1165
Denmark

Ole Birger Pedersen

Zealand University Hospital - Department of Clinical Immunology ( email )

Køge
Denmark

Henrik Hjalgrim

Statens Serum Institut - Department of Epidemiology Research ( email )

Denmark

Karina Banasik

Copenhagen University - Novo Nordic Foundation Center for Protein Research ( email )

Copenhagen
Denmark

Kristoffer S. Burgdorf

Copenhagen University - Novo Nordic Foundation Center for Protein Research ( email )

Copenhagen
Denmark

Mette Nyegaard

Aalborg University Hospital - Department of Clinical Immunology ( email )

Aalborg
Denmark

Jes Olesen

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark

Thomas Folkmann Hansen

University of Copenhagen - Department of Neurology ( email )

Glostrup
Denmark