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.

Introduction ICHD-3 criteria for chronic migraine (CM) include a mixture of migraine and tension-type-like headaches and do not account for patients who have a high frequency of migraine but no other headaches. Materials and methods Patients from the Danish Headache Center and their relatives with ICHD-3 defined CM were compared with patients with high frequency episodic migraine (HFEM). Danish registries were used to compare the socioeconomic impact in these two groups. A Russian student population was used to determine the generalizability of the number of patients fulfilling CM and the proposed diagnostic criteria for CM. Results There was no difference in the demographic profile between the two groups in the Danish cohort. The number of lifelong or annual attacks ( p > 0.3), comorbid diseases, or self-reported effect of triptans ( p = 1) did not differ. HFEM patients purchased more triptans than CM patients ( p = 0.01). CM patients received more early pension ( p = 0.00135) but did not differ from HFEM patients with regard to sickness benefit ( p = 0.207), cash assistance ( p = 0.139), or rehabilitation benefit ( p = 1). Discussion Patients with HFEM are comparable to CM patients with regard to chronicity and disability. We therefore suggest classifying CM as ≥ 8 migraine days per month (proposed CM), disregarding the need for ≥ 15 headache days per month. The proposed diagnostic criteria for CM approximately doubled the number of patients with CM in both the Danish and the Russian materials. Extending the definition of CM to include patients with HFEM will ensure that patients with significant disease burden and unmet treatment needs are identified and provided appropriate access to the range of treatment options and resources available to those with CM. Conclusion Patients with migraine on eight or more days but not 15 days with headache a month are as disabled as patients with ICHD-3 defined CM. They should be included in revised diagnostic criteria for chronic migraine.

BackgroundThe latest Genome-Wide Association Study identified 38 genetic variants associated with migraine. In this type of studies the significance level is very difficult to achieve (5 × 10− 8) due to multiple testing. Thus, the identified variants only explain a small fraction of the genetic risk. It is expected that hundreds of thousands of variants also confer an increased risk but do not reach significance levels. One way to capture this information is by constructing a Polygenic Risk Score. Polygenic Risk Score has been widely used with success in genetics studies within neuropsychiatric disorders. The use of polygenic scores is highly relevant as data from a large migraine Genome-Wide Association Study are now available, which will form an excellent basis for Polygenic Risk Score in migraine studies.ResultsPolygenic Risk Score has been used in studies of neuropsychiatric disorders to assess prediction of disease status in case-control studies, shared genetic correlation between co-morbid diseases, and shared genetic correlation between a disease and specific endophenotypes.ConclusionPolygenic Risk Score provides an opportunity to investigate the shared genetic risk between known and previously unestablished co-morbidities in migraine research, and may lead to better and personalized treatment of migraine if used as a clinical assistant when identifying responders to specific drugs. Polygenic Risk Score can be used to analyze the genetic relationship between different headache types and migraine endophenotypes. Finally, Polygenic Risk Score can be used to assess pharmacogenetic effects, and perhaps help to predict efficacy of the Calcitonin Gene-Related Peptide monoclonal antibodies that soon become available as migraine treatment.KeywordsMigraine genetics; Genome-Wide Association Studies; Polygenic Risk Score; pleiotropy; endophenotype.

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.

Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40–70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer’s disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.

ObjectiveThe 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.MethodsA 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.ResultsThe 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.InterpretationThis 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

Introduction Osmophobia has been suggested as an additional symptom of migraine without aura, and a high prevalence of osmophobia of up to 50% has been reported in the literature. We conducted a nosographic study of osmophobia in all migraineurs and tension-type headache patients and a field testing of suggested diagnostic criteria of osmophobia, presented in the appendix of the second edition of The International Classification of Headache Disorders and suggested by Silva-Néto et al. and Wang et al ., in migraine without aura and tension-type headache patients (n = 1934). Materials and methods Each patient received a validated semi-structured interview. All subjects fulfilled the diagnostic criteria of the second edition of The International Classification of Headache Disorders for migraine or tension-type headache. Statistical analyses were performed using statistical software R. The statistical R package "Caret" was used to construct a confusion matrix and retrieve sensitivity, which is defined as the suggested criteria's ability to correctly diagnose migraine without aura patients, and specificity, defined as the suggested criteria's ability to not wrongly diagnose tension-type headache patients. Results Osmophobia was present in 33.5% of patients with migraine with aura, in 36.0% of patients with migraine without aura, and in 1.2% of patients with tension-type headache. All migraineurs with osmophobia also fulfilled the current criteria for migraine by having nausea or photophobia and phonophobia. The appendix criteria had a sensitivity of 0.96 and a specificity of 0.99 for migraine without aura, and a sensitivity of 0.65 and a specificity of 0.99 for probable migraine without aura. Both the criteria by Silva-Néto et al. and Wang et al. had a sensitivity of 0.98 and a specificity of 0.99 for migraine without aura, and a sensitivity of 0.66 and a specificity of 0.99 for probable migraine without aura. Discussion This study demonstrates the remarkable specificity of osmophobia. The criteria by Silva-Néto et al. and Wang et al. both had a higher sensitivity than the appendix criteria for migraine without aura; all three criteria had a low sensitivity for probable migraine without aura. However, neither the appendix criteria nor the criteria by Silva-Néto et al. or Wang et al. added any extra patients that would not have been diagnosed by the current diagnostic criteria for migraine. Osmophobia is a valuable symptom that may be useful to differentiate between migraine without aura and tension-type headache in difficult clinical cases. Conclusion Our results do not suggest that alterations of the current diagnostic criteria for migraine without aura are needed.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent casecontrol cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.