Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine.

BACKGROUND AND PURPOSE: Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population-based genome-wide association study by Chasman et al. (Nat Genet 2011: 43: 695-698), three common variants were found to confer risk of migraine at a genome-wide significant level (P < 5 × 10(-8) ). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic-based Danish and Icelandic cohort. METHODS: The top association SNPs were assessed in 2523 cases and 38,170 controls, and a meta-analysis was performed, combining the discovery set with all the follow-up studies. Finally the confirmed SNPs were assessed in a genotype-phenotype analysis. RESULTS: Two out of three SNPs that showed genome-wide significant associations in the previous study: rs10166942 (near TRPM8) and rs11172113 (in LRP1) were significantly associated with migraine in the present study. The meta-analysis confirmed the previous three genome-wide significant associated SNPs (rs2651899, rs10166942 and rs11172113) to confer risk of migraine. In addition, the C-allele of rs2078371 (near TSPAN-2) also reached genome-wide significance for association with migraine [OR = 1.14; CI = (1.09-1.20); P = 2.55 × 10(-8) ]. CONCLUSION: TSPAN-2 encodes an integral membrane protein involved in oligodendrogenesis. This new finding supports the plausible implication of neuroglia in the pathophysiology of MO and MTA.

A genotype-phenotype analysis of the 8q22.1 variant in migraine with aura.

BACKGROUND AND PURPOSE: Although the genetics of familial hemiplegic migraine are being unraveled, this is not the case for the prevalent types of migraine. However, a recent genome wide association study (GWAS) reported an association of the single nucleotide polymorphism (SNP) rs1835740 and migraine. The aim of this study is to evaluate the association of clinical characteristics in migraine with aura (MA) with the newly discovered minor allele A of rs1835740 at 8q22.1. METHODS: Participants were recruited from the Danish Headache Center and from specialist practices during the periods 1999-2002 and 2005-2006, and diagnosed according to the International Classification of Headache Disorders (ICHD-II) using a validated physician-conducted semi-structured interview. A large number of clinical characteristics were systematically determined. Caucasians of Danish ancestry diagnosed with MA and successfully genotyped for the SNP rs1835740 were included. Patients with hemiplegic migraine were excluded. Blood samples were collected for extraction of genomic DNA and genotyped for the common susceptibility variant rs1835740. RESULTS: Six hundred and ninety one successfully genotyped MA patients with substantial description of their clinical characteristics were included. Two hundred and fifty one were heterozygous and 40 were homozygote for the variant marker. Carriers of the rs1835740 variant showed a non-significant tendency towards having a higher frequency of aura symptoms and a non-significant tendency towards milder migraine headache characteristics and fewer accompanying symptoms. These tendencies were not increased in homozygote carriers. CONCLUSION: None of the clinical characteristics of MA were significantly influenced by the common susceptibility variant on 8q22.1.

Trigger factors in migraine with aura.

The aim of the present study was to identify trigger factors in migraine with aura (MA). A total of 629 MA patients representative of the Danish population were sent a questionnaire listing 16 trigger factors thought to be relevant as well as space for free text. Distinction was made between attacks with or without aura within each patient. The questionnaire was returned by 522 patients of whom 347 had current MA attacks. In total 80% with current attacks (278/347) indicated that at least one factor triggered their migraine, and 67% (187/278) in this group indicated that they were aware of at least one factor often or always giving rise to an attack of MA. Forty-one per cent (113/278) had co-occurring attacks of migraine without aura (MO). Stress (following stress), bright light, intense emotional influences, stress (during stress) and sleeping too much or too little were the trigger factors mentioned by most. Attack frequency had little impact on the number of trigger factors. Women reported more trigger factors than men. Patients having attacks of both MA and MO reported more trigger factors for MO attacks than for MA attacks. In conclusion, 80% of patients with MA reported trigger factors and two-thirds of these reported at least one trigger factor often or always triggering an attack of MA. Patients should be educated to avoid these factors.

Efficacy and safety of tonabersat, a gap-junction modulator, in the acute treatment of migraine: a double-blind, parallel-group, randomized study.

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.