Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

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.publishedVersionPeer reviewe

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMigraine 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.US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) Finnish innovation fund Sitra Finska Lakaresallskapet Academy of Finland Sigrid Juselius Foundation Academy of Finland Appeared in source as:Academy of Finland Center of Excellence in Complex Disease Genetics Finnish Foundation for Cardiovascular Research Novo Nordisk Foundation Novocure Limited CANDY foundation (CEHEAD) South-Eastern Norway Regional Health Authorit

Assessment of Migraine History in Patients with a Transient Ischemic Attack or Stroke; Validation of a Migraine Screener for Stroke

BACKGROUND: To investigate the connection between migraine and stroke, a reliable screening tool to gather information about a person's migraine history is crucial. We studied the test-characteristics of a 5-question Migraine Screener for Stroke (MISS). METHODS: We included a random sample of patients with a transient ischemic attack or stroke who answered the MISS questionnaire when they were admitted to our hospital. After discharge, a semi-structured telephone interview was conducted to validate the migraine diagnosis with the International Classification of Headache Disorders, second-edition criteria as gold standard. RESULTS: Forty-nine (22.2%) of the 221 included patients were diagnosed with life-time migraine (38.5% women, 7.7% men). The sensitivity of all questions combined was 0.47 (95% CI 0.31-0.62), the specificity was 0.97 (95% CI 0.93-0.99), the positive predictive value (PPV) was 0.80 (95% CI 0.59-0.93) and the negative predictive value (NPV) was 0.87 (95% CI 0.82-0.92). One question related to the presence of headache accompanied by hypersensitivity to lights and sounds had a better sensitivity (0.96, 95% CI 0.85-1.00) and NPV (0.99, 95% CI 0.95-1.00) than all questions put together. For assessing migraine with aura, the question about visual disturbances had a good NPV (0.99, 95% CI 0.96-1.00), but a low PPV (0.38, 95% CI 0.24-0.53). CONCLUSIONS: The MISS questionnaire can be used by researchers to rule out migraine history in stroke patients. To prevent misclassification, especially for the aura symptoms, patients with a positive screener should be interviewed more extensively to confirm the migraine diagnosis

Brain atrophy following hemiplegic migraine attacks

Background Patients with hemiplegic migraine (HM) may sometimes develop progressive neurological deterioration of which the pathophysiology is unknown. Patient We report a 16-year clinical and neuroradiological follow-up of a patient carrying a de novo p.Ser218Leu CACNA1A HM mutation who had nine severe HM attacks associated with seizures and decreased consciousness between the ages of 3 and 12 years. Results Repeated ictal and postictal neuroimaging revealed cytotoxic oedema during severe HM attacks in the symptomatic hemisphere, which later showed atrophic changes. In addition, progressive cerebellar atrophy was observed. Brain atrophy halted after cessation of severe attacks, possibly due to prophylactic treatment with flunarizine and sodium valproate. Conclusion Severe HM attacks may result in brain atrophy and prophylactic treatment of these attacks might be needed in an early stage of disease to prevent permanent brain damag

Linking migraine frequency with family history of migraine

Background: Migraine is a complex genetic disorder that is brought about by multiple genetic and environmental factors. We aimed to assess whether migraine frequency is associated with genetic susceptibility. Methods: We investigated in 2829 migraine patients (14% males) whether ‘migraine frequency’ (measured as the number of migraine days per month) was related to ‘genetic load’ (measured as the number of parents affected with migraine) using a validated web-based questionnaire. In addition, we investigated associations with age-at-onset, migraine subtype, use of acute headache medication, and comorbid depression. Results: We found an association between the number of migraine days per month and family history of migraine for males (p = 0.03), but not for females (p = 0.97). This association was confirmed in a linear regression analysis. Also, a lower age-at-onset (p < 0.001), having migraine with aura (p = 0.03), and a high number of medication days (p = 0.006) were associated with a stronger family history of migraine, whereas lifetime depression (p = 0.13) was not. Discussion: Migraine frequency, as measured by the number of migraine days per month, seems associated with a genetic predisposition only in males. A stronger family history of migraine was also associated with a lower age-at-onset, a higher number of medication days, and migraine with aura. Our findings suggest that specific clinical features of migraine seem more determined by genetic factors

Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes

Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10−4), CACNA1H (p −16) and CACNA1I (p −16). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10−3), CACNA1H (p −16) and CACNA1I (p −16). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10−8; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease.</p

Registry of implants for the reconstruction of pelvic floor in males and females: A feasibility case series

Introduction: Most aspects of implant-assisted reconstruction of pelvic floor in males and females are under debate and the research is not standardized. Registries are supposed to shed light to the indications, surgical techniques and material properties and to establish a standardized evaluation. Methods: A working group was formed to create an online platform for registration and outcome measurement of implant-assisted operations for pelvic organ prolapse (POP) and female and male stress urinary incontinence (SUI). 20 patients with modified mesh materials were evaluated over 23 months 'follow up in the registry to prove the feasibility of the registry. For validation a previously published modified satisfaction, anatomy, continence, safety - S.(A.)C.S score was used. Results: A consensus was met on definitions and classifications of patient variables, surgical procedures and implants, as well as outcome parameters (efficacy, continence, satisfaction, complications). Different subgroup modules were formed in accordance with treated condition. The maximum score of cure was reached by 25-100% of patients depending on the indication. Conclusion: A prospective registry in accordance with IDEAL-D framework is justified for the evaluation and regulation of implants for pelvic floor reconstruction. (C) 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved

Supplemental material for Linking migraine frequency with family history of migraine

<p>Supplemental material for Linking migraine frequency with family history of migraine by Nadine Pelzer, Mark A Louter, Erik W van Zwet, Dale R Nyholt, Michel D Ferrari, Arn MJM van den Maagdenberg, Joost Haan and Gisela M Terwindt in Cephalalgia</p