Reappraisal of Sex Differences in Migraine

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