OBJECTIVE:Migraine is one of the most common pain disorders among women of childbearing age. While medical treatment might be necessary for some during pregnancy, non-pharmacological approaches, such as exercise, are generally recommended. We aimed to assess the association between migraine and exercise behaviours, adherence to the national recommendations for exercise, and the type of exercise undertaken during early pregnancy within a cohort of Danish women. METHODS:We performed a cross-sectional study using patient-reported questionnaire data from The Copenhagen Pregnancy Cohort (2013-2019). Logistic regression analyses were applied to assess associations between migraine and the selected outcomes, with adjustment for relevant confounders. RESULTS:We included 24,017 pregnancies. Women with migraine were more likely to refrain from exercise in early pregnancy compared to those without (46.4% vs 40.8%) (aOR 1.26, 95% CI 1.12-1.41). Additionally, they were more likely not to meet the national recommendations for exercise (62.9% vs 57.8%), (aOR 1.27, 95% CI 1.13-1.42). The differences were consistent among women with migraine with aura (MA) and migraine without aura (MO), respectively. Women with and without migraine participated in similar types of exercise during early pregnancy. CONCLUSIONS:Our findings indicate that women with migraine were less likely to engage in exercise and to adhere to the national recommendations of exercise, compared to those without. Findings were similar for women with MA and MO. The types of exercise performed did not differ between groups.

The pituitary adenylate cyclase-activating peptide (PACAP) pathway is a critical focus in the pathophysiology of several headache disorders. PACAP influences headache pathophysiology through interactions with distinct receptors (PAC1, VPAC1, and VPAC2) and pathways linked to neurovascular and hormonal regulation. Evidence supports its role in the modulation of trigeminal and parasympathetic systems, implicated in cluster headaches and menstrual migraine, and its involvement in sensitizing pain pathways post trauma in post-traumatic headaches. Early clinical trials targeting PACAP signaling show promise, with one study demonstrating efficacy in migraine prophylaxis. This narrative review synthesizes current evidence while addressing gaps in understanding PACAP's precise mechanisms. Future research should prioritize expanding the scope of PACAP-focused investigations across diverse headache types, aiming to establish it as a therapeutic target for several headache disorders. Success in ongoing and future trials could redefine headache management for millions of underserved patients worldwide.

INTRODUCTION:Migraine is a prevalent neurological headache disorder. Due to challenges associated with finding effective treatment, many individuals with migraine feel compelled to explore alternative treatment strategies, such as blood donation, hypothesized to provide migraine relief. METHODS:Through logistic, Poisson, and Cox regression methods, we examined the links between migraine and blood donation activities in two population cohorts: Danish blood donors in the Scandinavian Donations and Transfusions Database (SCANDAT-DK, N >1 million) and the Danish Blood Donor Study (N ~ 100,000). RESULTS:SCANDAT-DK analyses showed no link between migraine and the propensity to become a blood donor among males (odds ratio [OR]Males = 0.95 [95% Confidence Interval: 0.86-1.04], and a reduced propensity among females ORFemales = 0.88 [0.83-0.93]). The incidence of migraine was not reduced upon blood donation (standardized incidence ratio [SIR]Males = 0.94 [0.83-1.06]; SIRFemales = 1.04 [0.99-1.10]). Donors with migraine demonstrated longer intervals between donations (hazard ratio [HR]Males = 0.87 [0.85-0.91], HRFemales = 0.80 [0.78-0.82]), and an increased risk of donor lapse (ORMales = 1.23 [1.14-1.32]; ORFemales = 1.28 [1.22-1.33]). Results were corroborated in DBDS using self-reported migraine. Genetic predisposition to migraine associated with longer intervals in females (HRFemales = 0.98 [0.97-0.99]), but not in males. DISCUSSION:Our findings do not support the hypothesis that blood donation serves as a viable treatment strategy among migraine patients. Future prospective investigations may help to elucidate the underlying biological mechanisms by which blood donation may influence migraine pathology.

OBJECTIVE:To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex-specific factors. BACKGROUND:It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immune response and genetic diversity. METHODS:We performed a case-control study and included 13,210 individuals with migraine and 86,738 controls. All participants were part of the Danish Blood Donor Study Genomic Cohort. Participants were genotyped and 111 HLA alleles on 15 HLA genes were imputed. We examined the association between HLA alleles and migraine subtypes, considering sex-specific differences. RESULTS:We found no association between HLA alleles and migraine, neither overall, nor in the sex-specific analysis. In the migraine subtype analysis, three HLA alleles were associated with migraine without aura; however, these associations could not be replicated in an independent Icelandic cohort (2191 individuals with migraine without aura and 278,858 controls). Furthermore, we found no association between HLA alleles and migraine with aura or chronic migraine. CONCLUSION:We found no evidence of an association between the HLA system and migraine, suggesting that genetic factors related to the HLA system do not play a significant role in migraine susceptibility.

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13-1.27], p = 3.92 × 10-9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p < 0.05, two-sided). Participants for the replication were included from 2015 to 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders.

Importance There is a need for better recognition and more extensive research into menstrual migraine (MM) in the general population, and a revision of the diagnostic criteria for MM is warranted to move the field forward. Increased understanding of MM is crucial for improving clinical care, diagnosis, and therapy for MM. Objectives To assess the clinical characteristics of MM, including severity and treatment response, and to propose new diagnostic criteria for pure MM and menstrually related migraine. Design, Setting, and Participants This is a case-control study of Danish individuals with migraine. All individuals completed a 105-item validated diagnostic migraine questionnaire, sent via the Danish electronic mailing system (e-Boks) between May and August 2020, allowing diagnosis of pure MM and menstrually related migraine by the International Classification of Headache Disorders, Third Edition (ICHD-3). Data analysis was performed from September 2021 to November 2022. Exposure Diagnosis of migraine. Main Outcomes and Measures Clinical characteristics of women with MM and women with nonmenstrual migraine (non-MM) were compared using the ICHD-3 diagnostic criteria. A simulation of the risk of randomly misclassifying MM was based on number of migraine attacks during 3 menstrual cycles (3 × 28 days), and simulation analyses were performed using 100 000 permutations of random migraine attacks in migraine patients. Results A total of 12 618 individuals, including 9184 women, with migraine participated in the study. Among the women with migraine, the prevalence of MM was 16.6% (1532 women), and the prevalence of non-MM was 45.9% (4216 women). The mean (SD) age was 38.7 (8.7) years for women with MM and 37.0 (9.2) years for women with non-MM. Of the 1532 women with MM, 410 (26.8%) fulfilled ICHD-3 diagnostic criteria for pure MM, 1037 (67.7%) fulfilled ICHD-3 diagnostic criteria for menstrually related migraine, and 152 (9.9%) fulfilled proposed diagnostic criteria for rare pure MM. MM was associated with a higher frequency of migraine-accompanying symptoms (odds ratio [OR], 1.98; 95% CI, 1.71-2.29), more frequent (OR, 7.21; 95% CI, 5.77-9.03) and more severe (OR, 1.17; 95% CI, 1.13-1.21) migraine attacks, lower frequency of nonmigraine headache (OR, 0.31; 95% CI, 0.18-0.49), an overall greater response to treatment with triptans (OR, 1.66; 95% CI, 1.24-2.24), better improvement of migraine attacks during late pregnancy (OR, 5.10; 95% CI, 2.17-14.00), and faster reappearance of migraine attacks post partum (OR, 3.19; 95% CI, 2.40-4.25). Hormonal contraceptive-related MM was associated with a higher prevalence of migraine without aura than migraine related to spontaneous menstruation (OR, 1.82; 95% CI, 1.62-2.06). Otherwise, no differences between hormonal and spontaneous MM were observed. The risk of random diagnostic misclassification of ICHD-3 menstrually related migraine in women with high frequency episodic migraine was 43%. This risk was reduced to 3% when applying the proposed criteria for menstrually related migraine. Conclusions and Relevance In this case-control study, MM in the general population had clinical characteristics that were quantitively different from those of non-MM. Detailed descriptive data and suggested improved diagnostic criteria for pure MM and menstrually related migraine were provided.

An estimated 4–8% of all women, and 16–25% of women with migraine, have menstrual migraine (MM), which causes considerable disability, but is underdiagnosed and undertreated. We investigated the burden of disease, health-care seeking behavior, and treatment practices among women with MM, using social media. In 12 days, 6246 women answered an online survey, allowing for diagnosis of MM by the International Classification of Headache Disorders third edition (ICHD-3). In total, 47% had MM, 21% had non-menstrual migraine (nMM), and 15% had probable menstrual migraine (pMM). Among women with MM, 61% had missed out on school/work and 69% on family, leisure, or social activities in the last 3 months. Fifty-four percent had consulted a health-care practitioner about their MM, of whom thirty-seven percent had received information about medical treatment of MM. A total of 85% used medicine in connection with MM, either over-the-counter medication only (57%), prescription medication only (24%), or both. Social media offers an efficient and less expensive recruitment platform for population-based studies on MM and is a useful tool to raise public awareness about MM. Moreover, this study confirms the significant impact of MM on women’s everyday lives and the challenges it poses to their regular activities.

Background and purpose The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine.Methods In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache.Results Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found.Conclusion The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

Objective The objective of this study was to aggregate data for the first genomewide association study meta‐analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse‐variance genomewide association meta‐analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans‐ancestry meta‐analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome‐wide association, fine‐mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results The estimated single nucleotide polymorphism (SNP)‐based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta‐analysis, and one additional locus in the trans‐ethnic meta‐analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk‐taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation This first genomewide association study meta‐analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713–726

Objectives Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega.dataset:EGAD0 0001009756) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation.Data description Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high -quality summary level dataset of sequence variants.

BACKGROUND AND PURPOSE:Understanding migraine in a sex-specific manner is crucial for improving clinical care, diagnosis and therapy for both females and males. Here, data on sex differences are provided in the presentation of migraine in a large European-based population cohort, which is representative of the general population.METHODS:A population-based study of 62,672 Danish blood donors (both present and previous donors), of whom 12,658 had migraine, was performed. All participants completed a 105-item diagnostic migraine questionnaire sent via an electronic mailing system (e-Boks) between May 2020 and August 2020. The questionnaire allowed for correct diagnosis of migraine according to the International Classification of Headache Disorders, third edition.RESULTS:The migraine questionnaire was in-cohort validated and had a positive predictive value of 97% for any migraine, a specificity of 93% and a sensitivity of 93%. There were 9184 females (mean age 45.1 years) and 3434 males (mean age 48.0 years). The 3-month prevalence of migraine without aura was 11% in females and 3.59% in males. The 3-month prevalence of migraine with aura was 1.72% in females and 1.58% in males. In females, the age-related 3-month prevalence of migraine without aura increased markedly during childbearing age. In males, migraine both with and without aura showed less age variation. Females had a higher frequency of migraine attacks (odds ratio [OR] 1.22) but a lower frequency of non-migraine headaches (OR = 0.35). Females also had a greater intensity of pain, more unilateral and pulsatile pain, and exacerbation by physical activity (OR = 1.40-1.49) as well as more associated symptoms (OR = 1.26-1.98). Females carried 79% of the total migraine disease burden, which was almost exclusively driven by migraine without aura (77%), whilst there was no sex difference in the disease burden of migraine with aura.CONCLUSION:Females have more severe disease, resulting in a much higher migraine disease burden than indicated by prevalence alone.

Background Migraine with cranial autonomic symptoms is well described in the literature, but its prevalence in previous studies varies enormously. A precise estimate of the prevalence in a population-based material is important because migraine with cranial autonomic symptoms might represent an endophenotype, in which genetic and pathophysiological features differ from those without cranial autonomic features. The aim of the present study, therefore, was to estimate the prevalence in a big population-based sample using both questionnaire-based diagnosis (N = 12,620) and interview-based diagnosis (N = 302). We validate questionnaire-based diagnosis of migraine with cranial autonomic symptoms and develop the first diagnostic criteria for future research of this possible endophenotype. Methods The Danish Blood Donor Study included 127,802 persons who all received a migraine diagnostic questionnaire. Participants who had answered the diagnostic questionnaire constituted the Danish Migraine Population Cohort (N = 62,677) of whom 12,620 had migraine. The diagnostic migraine questionnaire included questions about the following cranial autonomic symptoms: Facial/forehead sweating, lacrimation, ptosis, conjunctival injection, rhinorrhea, nasal congestion, and miosis. Validation was performed by a follow-up semi-structured, purpose-built interview of 302 participants with migraine, where detailed questions were asked to ascertain the validity of the symptoms. Results The questionnaire-based prevalences of one, respectively two cranial autonomic symptoms were 57% and 31%. The semi-structured interview-based prevalences of one, respectively two symptoms were 44% and 22%. The most common symptoms were facial/forehead sweating (39%) and lacrimation (24%). The specificity of the questionnaire was 80% and the sensitivity was 68%. Correlation analysis showed a weak correlation between symptoms ranging from 0.07 – 0.41, and no clear clustering of symptoms was detected. We suggest the first diagnostic appendix criteria for genetic and epidemiological studies and tighter criteria for clinical and pathophysiological studies. We encourage further studies of severity and consistency of symptoms. Conclusion Migraine with cranial autonomic symptoms is prevalent in the general population. Suggested diagnostic appendix criteria are important for future studies of this possible migraine endophenotype. Keywords Migraine , cranial autonomic symptoms , diagnostic criteria

The real-world use of triptans in the treatment of migraine is disappointing. Only 12% of the Danish migraine population purchased a triptan between 2014 and 2019, and only 43% repurchased a triptan after first prescription. The aim of the present study was to assess whether physicians and patients adhere to the therapeutic guideline on acute migraine treatment. We interviewed 299 triptan experienced participants with migraine and 101 triptan naïve participants with migraine from the Danish Migraine Population Cohort, using a semi-structured questionnaire. Descriptive statistical analyses were used to study the association with triptan use and the assessed factors. Among triptan naïve participants with migraine, 64% had consulted their general practitioner about their migraine, of whom only 23% received information about the possibility of triptan treatment. Among triptan experienced participants, 77% had only tried one type of triptan. Only 12% could recall they had been informed by their general practitioner to try each triptan three times before giving up. Twenty percent were informed to try three different triptans in total, if the first did not work. In disagreement with the guideline, participants who reported a low pain reduction by a triptan had only tried one type of triptan. Our study shows a low adherence to therapeutic guideline for the attack treatment of migraine. There is a need for better education of general practitioners regarding treatment of migraine. Future campaigns should aim to inform both the public and the general practitioner about antimigraine treatments.

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).

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

BACKGROUND:Investigations of migraine among childhood cancer survivors have predominantly relied on self-reported information and hospital discharge diagnoses. Alone, both approaches are liable to bias. We used Danish nationwide registers to obtain data on both prescriptions of acute migraine medications (antimigraines) and hospital discharge diagnoses of migraine to assess the relative risk of migraine across a wider spectrum of migraine presentations than previously studied.METHODS:We followed a Danish population-based cohort of 7771 individuals with childhood cancer diagnosed in the period from Jan 1st, 1978 to Dec 31st, 2017, for risk of prescription antimigraine initiation and for risk of hospitalization due to migraine. Rates of hospitalization were assessed for the entire follow-up period whereas rates of antimigraine initiations were assessed in the period from Jan 1st, 1997, to Dec 31st, 2017. Relative to the general population without childhood cancer, standardized incidence ratios (SIRs) were calculated for each outcome.RESULTS:Individuals exposed to childhood cancer were at increased risk of antimigraine initiation (SIR of 1.24, 95% CI: 1.11-1.38) and of migraine hospitalization (SIR of 2.44, 95% CI: 1.87-3.12) from the day of their cancer diagnosis and up to 40 years after.CONCLUSIONS:Individuals diagnosed with childhood cancer have a higher risk of migraine of varying presentations, in addition to migraine resulting in hospitalization as previously reported. This potentially preventable problem warrants clinical attention.

BACKGROUND:The transition from episodic migraine to chronic migraine, migraine chronification, is usually a gradual process, which involves multiple risk factors. To date, studies of the genetic risk factors for chronic migraine have focused primarily on candidate-gene approaches using healthy individuals as controls.AIMS AND METHODS:In this study, we used a large cohort of migraine families and unrelated migraine patients (n > 2200) with supporting genotype and whole-genome sequencing data. We evaluated whether there are any genetic variants, common or rare, with a specific association to chronic migraine compared with episodic migraine.RESULTS:We found no aggregation of chronic migraine in families with a clustering of migraine. No specific rare variants gave rise to migraine chronification, and migraine chronification was not associated with a higher polygenic risk score. Migraine chronification was not associated with allelic associations with an odds ratio above 2.65. Assessment of effect sizes with genome-wide significance below an odds ratio of 2.65 requires a genome-wide association study of at least 7500 chronic migraine patients.CONCLUSION:Our results suggest that migraine chronification is caused by environmental factors rather than genetic factors.