One problem holding up development of better Migraine treatments is that there is still much that is not well understood about the disease. This includes the pathophysiology of Migraine and the genetics of Migraine.

Scientists have been certain for some time now that Migraine has a genetic component. In recent years, specific genes related to hemiplegic Migraine, a rare form of Migraine, have been located, but genetic links to other types of Migraine have been more elusive.

Now, a world-wide collaboration of researchers has identified the first-ever genetic risk factor associated with common* types of Migraine. The researchers, who looked at the genetic data of more than 50,000 people, have produced new insights into the triggers for Migraines attacks and they hope their research will open the door for novel medications to prevent Migraine attacks.

The team found that patients with a particular DNA variant on Chromosome 8 between two genes – PGCP and MTDH/AEG-1 – have a significantly greater risk for developing Migraine. The team also discovered a potential explanation for this link. It appears that the associated DNA variant regulates levels of glutamate – a neurotransmitter, which transports messages between nerve cells in the brain. The results suggest that an accumulation of glutamate in nerve cell junctions (synapses) in the brain may play a key role in the initiation of Migraine attacks. Prevention of the build up of glutamate at the synapse may provide a promising target for new Migraine treatments.

The study:

The researchers carried out what is known as a genome-wide association study (GWAS) to identify genome variants that could increase susceptibility to Migraine. The team compared the genomes of more than 3,000 people from Finland, Germany and The Netherlands with Migraine with the genomes of more than 10,000 non-Migraineurs, recruited from pre-existing studies, to spot differences that might account for one group's increased susceptibility to Migraine. To confirm their link, the team compared the genomes of a second group of more than 3,000 patients with more than 40,000 apparently healthy people.

Study summary:

This research article is quite complex, and the best summary of this research and its implications comes from the article itself:

"In summary, to our knowledge, we have identified the first robust genetic association to Migraine. As our cases were mainly selected from specialized headache clinics, subsequent studies are needed to establish the contribution of rs1835740 in population-based Migraine cohorts. These population-based cohorts may represent a different severity spectrum and possibly also a somewhat different underlying combination of genetic susceptibility variants. The effect of rs1835740 is stronger in individuals with Migraine with aura than in those with Migraine without aura, but further studies are needed to confirm the role of the variant in different Migraine subgroups. This variant explains only a small fraction of the overall genetic variance in Migraine, and future GWAS (Genome-Wide Association Studies), perhaps with different ascertainment schemes, will likely identify additional loci explaining more of the genetic variance."¹

Comments from the researchers:

Aarno Palotie, chair of the International Headache Genetics Consortium at the Wellcome Trust Sanger Institute, which spearheaded the study, commented:

"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... 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."³  and

"We have found this association primarily with Migraine with aura. More studies need to be done to verify how widely this is true for other forms of Migraine... When you use genome-wide association studies, you often land in an area that you have no clue what's actually done there. In this case, we were lucky. Both of these genes are related to the glutamate balance in the body and the brain. We further know that one of these genes regulate an additional gene involved in glutamate regulation. What it means is there are many, many more genes that predispose us to Migraines."²

Professor Christian Kubisch of University of Ulm, Germany, coauthor of the study, said:

"Although we knew that the EAAT2 gene has a crucial role to play in neurological processes in human 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. 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."³

Dr. Gisela Terwindt of Leiden University Medical Center, another senior author of the study, remarked:

"Although the patients in the study were all diagnosed with common* Migraine, they were largely recruited from 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. In the future, we should look at associations across the general population, including also people who are less severely affected."³

Summary and comments:

Progress always seems slow to people suffering with conditions such as Migraines and other headache disorders, or any disease or condition. Still, given that the mapping of the human genome took 13 years and wasn't completed until 2003, there has been amazing progress in identifying genetic connections to Migraine.

Of course, when we see research like this, we all hope it's going to lead to a cure for the disease. And, it may, someday. That's certainly a possible long-term outcome. Short-term, this type of research is likely to lead to new treatments, treatments truly developed for Migraine.

The authors caution that further study will be needed, both into the DNA variant and its regulatory effect on the genes flanking it, to shed light on the mechanism for the occurrence of Migraine attacks, and further research to find additional contributing genetic factors. The authors also suggest that broader population samples should be interrogated.

Still, this research is progress. It's also a different kind of progress than much of the research we've been following. For example: We've been following research on medications for Migraine and headache prevention, but most of this research has centered around medications originally developed for other conditions. Some medications are being developed specifically for Migraine prevention, but they're still far from ready for marketing, and at this time, there are NO medications on the market that were specifically developed for Migraine prevention. Research such as this new study may well be the key developing medications specifically for that purpose.

* "Common," in this context, does not refer to the older term "common Migraine," which is now called Migraine without aura. In this context, "common" means the more commonly occurring forms of Migraine as opposed to the rarer forms such as hemiplegic Migraine.

____________
Resources:

¹ Verneri Anttila, Hreinn Stefansson, Mikko Kallela, Unda Todt, Gisela M Terwindt, M Stella Calafato, Dale R Nyholt, Antigone S Dimas, Tobias Freilinger, Bertram Müller-Myhsok, Ville Artto, Michael Inouye, Kirsi Alakurtti, Mari A Kaunisto, Eija Hämäläinen, Boukje de Vries, Anine H Stam, Claudia M Weller, Axel Heinze, Katja Heinze-Kuhn, Ingrid Goebel, Guntram Borck, Hartmut Göbel, Stacy Steinberg, Christiane Wolf, Asgeir Björnsson, Gretar Gudmundsson, Malene Kirchmann, Anne Hauge, Thomas Werge, Jean Schoenen, Johan G Eriksson, Knut Hagen, Lars Stovner, H-Erich Wichmann, Thomas Meitinger, Michael Alexander, Susanne Moebus3, Stefan Schreiber, Yurii S Aulchenko, Monique M B Breteler, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Päivi Tikka-Kleemola, Salli Vepsäläinen, Susanne Lucae, Federica Tozzi, Pierandrea Muglia, Jeffrey Barrett, Jaakko Kaprio, Markus Färkkilä, Leena Peltonen, Kari Stefansson, John-Anker Zwart, Michel D Ferrari, Jes Olesen, Mark Daly, Maija Wessman, Arn M J M van den Maagdenberg, Martin Dichgans, Christian Kubisch, Emmanouil T Dermitzakis, Rune R Frants, & Aarno Palotie for the International Headache Genetics Consortium. "Genome-wide association study of Migraine implicates a common susceptibility variant on 8q22.1" Nature Genetics, advance online publication. Received 1 March; accepted 2 July; published online 29 August 2010; doi:10.1038/ng.652.

² Goodwin, Jennifer. "New Migraine Gene Discovered." HealthDay. U.S.News Health. August 29, 2010.

³ Press Release. "First genetic link to common Migraine exposed." Wellcome Trust Sanger Institute. August 29, 2010.

⁴ Human Genome Project Web Site.

Medical review by John Claude Krusz, PhD, MD

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© Teri Robert, 2010. Last updated September 29, 2010.

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