A worldwide collaboration of researchers has identified a genetic risk factor associated with common types of migraine. The researchers, who looked at genetic data of more than 50,000 people, have also produced insights into the triggers for migraine attacks.
Although scientists have previously described genetic mutations giving rise to rare and extreme forms of migraine, this is reportedly the first time a team has identified a genetic variant giving rise to the common form of the condition.
"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," says Aarno Palotie, M.D., Ph.D., chair of the International Headache Genetics Consortium at the Wellcome Trust Sanger Institute, which spearheaded the study. Results were published August 29 in Nature Genetics in a paper titled "Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1." Wellcome Trust investigators were joined by scientists from over 40 centers around the world.
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 variant appears to alter the activity of MTDH/AEG-1 in cells, which regulates the activity of the EAAT2 gene; the EAAT2 protein is responsible for clearing glutamate from brain synapses in the brain. The results suggest that an accumulation of glutamate in synapses in the brain may play a key role in the initiation of migraine attacks.
EAAT2 has previously been linked with other neurological diseases including epilepsy, schizophrenia, and various mood and anxiety disorders. "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," says co-senior author of the study Christian Kubisch of University of Ulm, Germany (previously at the University of Cologne where he conducted his research for this study).
The scientists carried out a genome-wide association study, comparing the genomes of more than 3,000 people from Finland, Germany, and The Netherlands with migraine with the genomes of more than 10,000 nonmigraineurs, recruited from pre-existing studies. To confirm their link, the team compared the genomes of a second group of more than 3,000 patients with over 40,000 apparently healthy people.
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 into additional contributing genetic factors.
The authors also suggest that broader population samples should be interrogated. "Although the patients in the study were all diagnosed with common migraine, they were largely recruited from specialist headache clinics," says and Gisela Terwindt, M.D., Ph.D., of Leiden University Medical Center, another senior author of the study. "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."