An international consortium of geneticists and headache researchers has identified a genetic variant in people who are prone to a common form of migraine. Published in the journal Nature Genetics, the study was financed in part by the EUROHEAD ('Migraine genes and neurobiological pathways') project, which was financed with EUR 3.2 million under the Sixth Framework Programme (FP6). There are seven types of migraine headache, all of them extremely painful. During migraine attacks, sufferers are sensitive to light and sound and often experience nausea, vomiting or temporary loss of vision. Several triggers are associated with the condition including stress and lack of sleep. Changes in hormone levels can also trigger attacks; women are more affected than men. An estimated 8% of males and 17% of females in Europe regularly experience migraines. In recent years, scientists have come to understand that a person's susceptibility depends primarily on genetic factors. Genetic mutations that lead to rare and extreme forms of migraine have recently been uncovered, but the genetic factors underlying the common form of migraine have until now been poorly understood. In this latest research, a genome-wide association study, scientists from 40 research centres around Europe combined their efforts to study genetic data from over 50,000 people. Initially, they compared the genomes of 2,731 migraine sufferers from Germany, the Netherlands and Finland with those of 10,747 controls; to confirm their findings, they then compared the genomes of another 3,202 patients with 40,062 controls. The team found that patients who have a specific DNA (deoxyribonucleic acid) variant located on Chromosome 8 (between two genes, PGCP and MTDH/AEG-1) were more likely to experience migraines. 'This is the first time we have been able to peer into the genomes of many thousands of people and find genetic clues to understand common migraine,' said Dr Aarno Palotie, Chair of the International Headache Genetics Consortium at the Wellcome Trust Sanger Institute in the UK. The researchers showed that the genetic variant plays a key role in regulating glutamate, a neurotransmitter. Specifically, it can alter the activity of MTDH/AEG-1, which regulates the activity of the EAAT2 gene. The EAAT2 protein normally clears glutamate from brain synapses (this protein has already been linked to neurological diseases including epilepsy and schizophrenia). The authors believe that the link between the variant (called rs1835740) and migraine is that poor glutamate regulation could lead to an accumulation of the chemical in the brain's synapses, making a person increasingly sensitive to migraine triggers. They suggest that a new therapeutic approach could be to prevent glutamate build-up. 'Although we knew that the EAAT2 gene has a crucial role to play in neurological processes in humans - and potentially in the development of migraine - until now, no genetic link has been identified to suggest that glutamate accumulation in the brain could play a role in common migraine,' said Professor Christian Kubisch of the University of Ulm in Germany. 'This research opens the door for new studies to look in depth at the biology of the disease and how this alteration in particular may exert its effect.' 'Studies of this kind are possible only through large-scale international collaboration, bringing together the wealth of data with the right expertise and resources so that we could pick out this genetic variant. This discovery opens new doors to understand common human diseases,' Dr Palotie pointed out. The authors caution that further study of the DNA variant and its effect on surrounding genes is needed to understand the mechanism behind migraine attacks. 'The variant explains only a small fraction of the overall genetic variance in migraine,' the study concludes. Future genome-wide association studies will hopefully shed light on more of the genetic variance. Future studies will also examine broader population samples, as the current study relied on data from people who had consulted specialist headache clinics. 'Because they are attending headache clinics they are likely to represent only the more extreme end of those who suffer common migraine,' explained Dr Gisela Terwindt of Leiden University Medical Center in the Netherlands. 'In the future, we should look at associations across the general population, including also people who are less severely affected.'
Finland, United Kingdom