Chronic migraine: Genetics or environment?
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ABSTRACT: 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.
SUBMITTER: Chalmer MA
PROVIDER: S-EPMC8247872 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Migraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology. FINDINGS:Migraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants. With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology. CONCLUSIONS:The complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.
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Project description:Migraine with and without aura (MA and MO, respectively) have a strong genetic basis. Different approaches using linkage-, candidate gene- and genome-wide association studies have been explored, yielding limited results. This may indicate that the genetic component in migraine is due to rare variants; capturing these will require more detailed sequencing in order to be discovered. Next-generation sequencing (NGS) techniques such as whole exome and whole genome sequencing have been successful in finding genes in especially monogenic disorders. As the molecular genetics research progresses, the technology will follow, rendering these approaches more applicable in the search for causative migraine genes in MO and MA. To date, no studies using NGS in migraine genetics have been published. In order to gain insight into the future possibilities of migraine genetics, we have looked at NGS studies in other diseases and have interviewed three experts in the field of genetics and complex traits. The experts' ideas suggest that the preferred NGS approach depends on the expected effect size and the frequency of the variants of interest. Family-specific variants can be found by sequencing a small number of individuals, while a large number of unrelated cases are needed to find common and rare variants. NGS is currently hampered by high cost and technical problems concurrent with analyzing large amounts of data generated, especially by whole genome sequencing. As genome-wide association chips, exome sequencing and whole genome sequencing gradually become more affordable, these approaches will be used on a larger scale. This may reveal new risk variants in migraine which may offer previously unsuspected biological insights.
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Project description:PURPOSE OF REVIEW:Migraine is a primary headache disorder and one of the most common and disabling neurological diseases worldwide. Genome-wide association studies have identified ≈40 genetic loci associated with migraine. How these and other genetic findings are used to expand our knowledge on the pathophysiological mechanism of common migraine and rare migraine variants will be discussed. RECENT FINDINGS:The genetic load, based on common polygenic variation, is higher in familial migraine cases than in nonfamilial cases, and higher for migraine with aura and hemiplegic migraine. Migraine shares common genetic variant risks with depression. Specific clinical features of common migraine seem to be determined by genetic factors. A stronger family history of migraine is associated with lower age-at-onset, higher frequency and number of medication days and the migraine with aura subtype. Mild hemiplegic migraine is likely caused by complex polygenic interaction of multiple gene variants and environmental factors, like in common migraine subtypes. Phenotypical features in hemiplegic migraine patients may guide physicians in providing adequate genetic counseling. SUMMARY:Integration of genetic, phenotypic and epigenetic data will help to identify the biological mechanisms by which genetic factors contribute to migraine pathogenesis. Recent studies show the impact of genetics on clinical features and comorbidities in migraine and may guide clinicians to an adequate genetic advice for patients.
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Project description:Chronic migraine (CM) is defined as headache occurring more than fifteen days/month for at least three consecutive months, with headache having the clinical features of migraine without aura for at least eight days per month. Recently, new treatment options became available in chronic migraine patients. Topiramate is effective in chronic migraine, in the presence or absence of medication overuse, and/or other migraine prophylaxis. Efficacy of onabotulinumtoxin A as a preventive treatment of chronic migraine has been shown in the PREEMPT studies. Occipital nerve stimulation (ONS) is an invasive treatment for refractory chronic headaches. ONS has encouraging results in refractory chronic migraine patients in commercially funded, multi-centre randomized trials.
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Project description:BackgroundLongitudinal migraine studies have rarely assessed headache frequency and disability variation over a year.MethodsThe Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a cross-sectional and longitudinal Internet study designed to characterize the course of episodic migraine (EM) and chronic migraine (CM). Participants were recruited from a Web-panel using quota sampling in an attempt to obtain a sample demographically similar to the US population. Participants who passed the screener were assessed every three months with the Core (baseline, six, and 12 months) and Snapshot (months three and nine) modules, which assessed headache frequency, headache-related disability, treatments, and treatment satisfaction. The Core also assessed resource use, health-related quality of life, and other features. One-time cross-sectional modules measured family burden, barriers to medical care, and comorbidities/endophenotypes.ResultsOf 489,537 invitees, we obtained 58,418 (11.9%) usable returns including 16,789 individuals who met ICHD-3 beta migraine criteria (EM (<15 headache days/mo): n = 15,313 (91.2%); CM (? 15 headache days/mo): n = 1476 (8.8%)). At baseline, all qualified respondents (n = 16,789) completed the Screener, Core, and Barriers to Care modules. Subsequent modules showed some attrition (Comorbidities/Endophenotypes, n = 12,810; Family Burden (Proband), n = 13,064; Family Burden (Partner), n = 4022; Family Burden (Child), n = 2140; Snapshot (three months), n = 9741; Core (six months), n = 7517; Snapshot (nine months), n = 6362; Core (12 months), n = 5915). A total of 3513 respondents (21.0%) completed all modules, and 3626 (EM: n = 3303 (21.6%); CM: n = 323 (21.9%)) completed all longitudinal assessments.ConclusionsThe CaMEO Study provides cross-sectional and longitudinal data that will contribute to our understanding of the course of migraine over one year and quantify variations in headache frequency, headache-related disability, comorbidities, treatments, and familial impact.
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Project description:ObjectiveTo compare the clinical phenotype of patients with chronic migraine (CM) to patients with new daily persistent headache of the chronic migraine subtype (NDPH-CM).MethodsA study was conducted of CM (n = 257) and NDPH-CM (n = 76) from a tertiary headache center in the UK, and in the US of patients with daily CM (n = 60) and NDPH-CM (n = 22).ResultsFrom the UK cohort, the age of first headache onset was lower in CM (mean ± SD: 16 ± 12 years) than in NDPH-CM (mean ± SD: 23 ± 14 years; p < 0.001). There was a greater number of associated migrainous symptoms in CM compared to NDPH-CM (median and interquartile range: 6, 5-8 vs. 5, 4-7; p < 0.001). A family history of headache was more common in CM compared to NDPH-CM (82%, 202/248, vs. 53%, 31/59; p < 0.001). In the US cohort there were no differences. Osmophobia (B = -1.08; p = 0.002) and older age at presentation to the clinic (B = -0.06; p = 0.001) were negative predictors of NDPH-CM.ConclusionNDPH-CM is relatively less migrainous than CM in the UK cohort. Family history of headache is less common in NDPH-CM, with negative predictors for NDPH-CM including osmophobia and older age of presentation to the clinic. More work is required to understand the chronic migraine phenotype of new daily persistent headache.
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Project description:To assess the prevalence and possible pathogenetic involvement of raised intracranial pressure in patients presenting with unresponsive chronic migraine (CM), we evaluated the intracranial opening pressure (OP) and clinical outcome of a single cerebrospinal fluid withdrawal by lumbar puncture in 44 consecutive patients diagnosed with unresponsive chronic/transformed migraine and evidence of sinus stenosis at magnetic resonance venography. The large majority of patients complained of daily or near-daily headache. Thirty-eight (86.4%) had an OP >200 mmH2O. Lumbar puncture-induced normalization of intracranial pressure resulted in prompt remission of chronic pain in 34/44 patients (77.3%); and an episodic pattern of headache was maintained for 2, 3 and 4 months in 24 (54.6%), 20 (45.4%) and 17 (38.6%) patients, respectively. The medians of overall headache days/month and of disabling headache days/month significantly decreased (p < 0.0001) at each follow-up versus baseline. Despite the absence of papilledema, 31/44 (70.5%) patients fulfilled the ICHD-II criteria for "Headache attributed to Intracranial Hypertension". Our findings indicate that most patients diagnosed with unresponsive CM in specialized headache clinics may present an increased intracranial pressure involved in the progression and refractoriness of pain. Moreover, a single lumbar puncture with cerebrospinal fluid withdrawal results in sustained remission of chronic pain in many cases. Prospective controlled studies are needed before this procedure can be translated into clinical practice. Nonetheless, we suggest that intracranial hypertension without papilledema should be considered in all patients with almost daily migraine pain, with evidence of sinus stenosis, and unresponsive to medical treatment referred to specialized headache clinics.
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Project description:ObjectiveTo identify patterns of noncephalic pain comorbidity in people with episodic migraine (EM; <15 headache-days per month) and chronic migraine (CM; ≥15 headache-days per month) and to examine whether the presence of noncephalic pain is an indicator for the 3-month onset or persistence of CM.MethodsData from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, a prospective, web-based study with cross-sectional modules embedded in a longitudinal design, were analyzed at baseline and the 3-month follow-up. Relationships between the number of noncephalic pain sites and 3-month onset of CM or persistent CM were assessed.ResultsOf 8,908 eligible respondents, 8,139 (91.4%) had EM and 769 (8.6%) had CM at baseline. At 3 months, the incidence of CM among those with baseline EM was 3.4%. When adjusted for demographics and headache-day frequency, the odds of CM onset among those with baseline EM increased by 30% (95% confidence interval [CI] 1.21-1.40, p < 0.001) for each additional noncephalic pain site at baseline. Among those with CM at baseline, 50.1% had persistent CM at the 3-month follow-up. After adjustment for demographics, individuals with CM were 15% (95% CI 1.07-1.25, p < 0.001) more likely to have persistent CM for each additional noncephalic pain site at baseline.ConclusionsThese results suggest that noncephalic pain may be a marker for headache chronicity that could be used to identify people with EM at risk of the onset of CM and people with CM at risk of persistent CM.
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Project description:Perimenopause is linked to increased migraine (Mg), especially menstrual Mg (MMg), influenced by hormonal changes. Compared to nonmenstrual attacks, menstrual attacks are more disabling and less responsive to treatment. Women with perimenstrual estrogen withdrawal have been linked to Mg during menstruation, whereas Mg during perimenopause has been linked to unpredictable fluctuations in estrogen levels. It has been widely established that female sex hormones play a role in Mg, but how it occurs remains unclear. This narrative review was identified using Medline and PubMed searches between 1946 and 2021. Search terms included "headache," "migraine," "menstrual migraine," "menstruation," "menopause," "perimenopause," "estrogen," and "progesterone." This article focuses on the candidate genes and female hormones that play a role in MMg. More study is necessary to understand better the environmental components that play a critical role in disease development. Currently, there is insufficient clinical evidence to support the function of menstrual Mg. The specific research facts examined MMg unique candidate genes and female hormonal factors that support their association and found MMg etiologic processes for generating an early diagnostic marker.
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