For the first time, a risk factor for widespread migraine forms has been discovered in the genome

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Kiel, Cologne, Ulm – August 31, 2010. Scientists from the Kiel Pain Clinic and the University of Cologne/Ulm, in collaboration with researchers from, among others, the Wellcome Trust Sanger Institute (Cambridge), Ludwig Maximilian University of Munich, and Leiden University Medical Center, have for the first time identified a genetic risk factor associated with migraine with and without aura. The genetic variant found on chromosome 8 controls the amount of the neurotransmitter glutamate at nerve synapses via the neighboring genes PGCP and MTDH. Glutamate activates important nerve functions such as attention, memory, concentration, and perception. This new discovery is considered crucial for understanding the onset of the most common migraine attacks. It offers new insights into the causes and treatment options for this widespread condition. The international research team describes these entirely unexpected findings in the current issue of the journal "Nature Genetics."

Through a unique international collaboration of 65 researchers from 13 countries in the world's largest migraine study to date, a gene variant has been discovered for the first time that is associated with the most common forms of migraine. Previous studies had only been able to identify gene alterations in rare subtypes of migraine with aura. The newly discovered gene variant on chromosome 8 is found in migraine with or without accompanying neurological symptoms.

In previous studies, researchers had already discovered gene loci responsible for very severe but rare subtypes of migraine. However, it remained unclear which risk factors in the genetic material were responsible for the widespread common migraine, that is, migraine with and without aura. In the search for the key to common migraine, the genomes of over 6,000 migraine patients were compared with those of healthy control subjects. Researchers from over 13 countries collaborated internationally. The patient group from the Kiel Pain Clinic was one of the largest subgroups within the network, enabling the current identification of the gene variant. To compile the data, a research group from the Kiel Pain Clinic collected and classified blood samples from affected patients and their family members over several years in Germany. The project was also supported in Schleswig-Holstein by the AOK Schleswig-Holstein health insurance company. These samples were crucial for the discovery of these entirely new findings.

Completely unexpectedly, basic researchers were able to identify a variant on chromosome 8, called rs1835740, as the first known genetic risk factor for migraine. In the initial study, genetic material from over 2,500 migraine patients and 10,000 healthy individuals was compared. Due to the unexpected finding, this gene locus was re-examined in a second, very extensive replication study involving over 3,200 additional migraine patients and 40,000 control subjects. The international migraine network was thus able to confirm its initial suspicion. This provides the first evidence that the discovered gene variant plays a fundamental role in the development of the widespread disease migraine.

The newly discovered regulatory circuits could help explain some of the clinical characteristics of migraine. Affected individuals are characterized by a high level of attention. They are able to differentiate stimuli very precisely. They can focus their attention on several stimuli simultaneously. Furthermore, they do not become accustomed to repeated stimuli but remain focused on recurring ones. They are characterized by a particularly high sensitivity to perception and a high readiness of their nervous system for activation.


Due to a genetically determined high glutamate level, it appears that the transmission of nerve impulses across the synaptic cleft between nerves can be very rapid, sustained, and intense. Stress and irregular daily rhythms are the strongest migraine triggers. If the nervous system is activated too strongly, too intensely, too excessively, and too suddenly, this can initially lead to overactivation and ultimately to depletion of neurotransmitters. Nerve control could become disrupted, secondarily releasing inflammatory substances within the nervous system. These can lead to painful inflammation of the blood vessels in the meninges, causing the throbbing and pulsating migraine headache.

The research approaches now discovered will make it easier to intervene more effectively in the underlying causes of migraines in the future. Current clinical studies have shown that those suffering from frequent attacks are characterized by a high sensitivity of the nervous system and the pain perception system. Both behavioral and experiential factors that contribute to the excessive activation of glutamate levels could now be specifically addressed in clinical research programs. The development of specific classes of substances that normalize glutamate levels could represent further steps toward the successful prevention of migraine attacks in the future.

“These new findings open up entirely new visions and development possibilities for the migraine therapy of the future. The discovery opens new doors in understanding, but also, and especially, in treating the widespread disease of migraine,” explains the study's co-author, Prof. Dr. Hartmut Göbel from the Kiel Pain Clinic. These new results were only made possible through international research collaboration and the integration of clinical knowledge with basic research.

“It was completely unexpected that the gene locus now discovered has significance for migraine risk,” says the study’s co-author, Prof. Christian Kubisch from the University of Cologne (since August 1, 2010, University of Ulm). Further studies will be conducted to clarify which additional DNA variants are relevant to the development of migraines.

migraine

Migraine is a widespread condition and one of the most common disorders of the human nervous system. It causes significant disability in affected individuals and can occur at any age, peaking in the fourth decade of life. One in three women and one in twelve men may be affected. Migraines occur episodically in attacks, each lasting up to three days. The headache is throbbing and pulsating. Physical activity intensifies the pain, often resulting in bed rest. Attacks can be accompanied by nausea, vomiting, sensitivity to noise and light, and other severe symptoms. The frequency of attacks varies considerably. Patients with chronic migraine are particularly severely affected, experiencing migraine attacks on more than 15 days per month. These patients have little time to recover between attacks, and their entire experience and behavior can be significantly impacted by the condition. Migraine is considered one of the most costly diseases of the nervous system. The World Health Organization considers them to be among the most disabling diseases.

Migraine is now understood as a progressive disease of the central nervous system. Prolonged and frequent migraine attacks cause structural changes in the nervous system, thereby increasing the likelihood of a number of associated conditions. These include, in the neurological field, epilepsy, medication-overuse headache, and stroke; in the psychiatric field, depression, anxiety disorders, and panic disorders; and in the internal medicine field, heart attacks, coronary artery disease, and hypertension. The constant overactivation of the nervous system due to elevated glutamate levels could also play a crucial role in the development of other diseases besides migraine. The recently discovered genetic risk factor on chromosome 8 could be relevant as a common basis for these diverse conditions.

Financial support

The researchers from the Kiel Pain Clinic and their colleagues from the Institute of Human Genetics in Cologne received significant financial support for their work through funding from the National Genome Research Network (NGFN-plus) , the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), and the Center for Molecular Medicine Cologne (ZMMK). The study was published on August 29, 2010, in the renowned scientific journal Nature Genetics.

Participating centers

The complete list of participating centers can be found on the Nature website: http://www.nature.com

Details of the publication

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1
Nature Genetics doi:10.1038/ng.652
Published online August 29, 2010

Investigators from the International Headache Genetics Consortium report the first genetic risk factor for migraine in Nature Genetics. In an attempt to identify genetic variants associated with common forms of migraine (migraine with and without aura), the authors carried out a two-stage genome-wide association study (GWAS) in seven European migraine case collections (six clinic-based and one population-based) which included 3,279 migraineurs (1,124 Finnish, 1,276 German and 879 Dutch individuals) recruited from headache clinics and 10,747 genotyped population-matched controls recruited from preexisting population-based GWAS. In the replication stage, 3,202 cases and 40,062 population-matched controls from Iceland, Denmark, The Netherlands and Germany were studied.

They identified a DNA sequence variant (rs1835740) on chromosome 8q22.1 to be associated with migraine. The effect appeared stronger for migraine with aura compared to migraine without aura. rs1835740 is located between two genes involved in glutamate homeostasis, MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). MTDH regulates SLC1A2, the gene that regulates the major glutamate transported in the brain. The authors speculate that accumulation of excess glutamate in the synaptic cleft through downregulation of EAAT2 or an increase in PGCP activity (or both) would provide a putative mechanism for the occurrence of migraine attacks, based on the pivotal role of glutamate in the pathogenesis of cortical spreading depression (CSD) and central sensitization. The authors acknowledged the need for further studies involving migraine subjects in the general population as this study evaluated subjects from headache clinics.

This is a major step forward in migraine science. It is the first study to identify a genetic risk factor for the common subtypes of migraine, and provides some support for the general concept of migraine as state of brain hyperexcitability. It also supports previous research findings on the potential role of glutamate in migraine, especially as an important candidate with regards to the genesis of (CSD) and progression of attacks, as well as progression of the disease (central sensitization). For more than a decade, drug discovery programs have pursued and continued to search for glutamate receptor modulators for both acute and preventive migraine medications, with mixed success. The complexity of interfering with glutamate transport of processing in the brain relates to the importance of this excitatory neurotransmitter in the normal physiological processes in the brain, including learning and memory, as well as the fact that there are numerous glutamate receptor subtypes with different physiological function. Nevertheless, further work in determining the precise role of this minor allele, including replicating the study in other populations outside Europe, may provide key insights into the relevance of this genetic variant in terms of the pathogenesis of migraine as well as future targets for novel therapies.