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 therapeutics 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 chemical, known as 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 novel therapeutics to ease the burden of the disease.

Migraine affects approximately one in six women and one in twelve men, and has been estimated to be the most expensive brain disorder to society in the EU and US. A US report measures its economic costs as similar to those of diabetes and WHO lists it as one of the top 20 diseases with years lived with disability (YLDs).

Although researchers have in the past described genetic mutations giving rise to rare and extreme forms of migraine, this is 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,” said Dr Aarno Palotie, chair of the International Headache Genetics Consortium at the Wellcome Trust Sanger Institute and senior researcher at the Institute for Molecular Medicine Finland FIMM, which spearheaded the study.

“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.”

The researchers carried out what is known as a genome-wide association study (GWAS) to zoom in on genome variants that could increase susceptibility to migraine. The team compared the genomes of more than 3000 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 3000 patients with more than 40,000 apparently healthy people.

The statistical analysis revealed that a DNA variation found between the PGCP and MTDH/AEG-1 genes on chromosome 8 appears to be associated with increased susceptibility to common 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. EAAT2 has previously been linked with other neurological diseases, including epilepsy, schizophrenia and various mood and anxiety disorders.

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.

Nature Genetics: Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Of the 2,500 human genomes to be sequenced, 100 are Finns that have been recruited by FIMM.  The 100 Finnish genomes will give more insight into the distinct characteristics of the Finnish population, which have been recently studied at FIMM as part of The Finnish Gene Atlas project.  In addition, rare variants identified in the Finnish genomes will assist researchers in ascertaining disease-causing genetic factors in Finnish samples.  The Finnish participation in the project was initiated by the late Academician Leena Peltonen-Palotie and is currently headed by Professor Aarno Palotie of The Wellcome Trust Sanger Institute (WTSI) and FIMM.  Before leaving to WTSI for her postdoc, Dr. Karola Rehnström collected the Finnish samples at FIMM.

For further information, please contact:

Dr. Elisabeth Widén, Institute for Molecular Medicine Finland (FIMM), University of Helsinki
Tel. +358 50 3812738
E-mail: Elisabeth.widen@helsinki.fi

Reference: Widén & al. Distinct Variants at LIN28B Influence Growth in Height from Birth to Adulthood.  American Journal of Human Genetics, 15 April, 2010 (on line).

Hundreds of thousands of gene markers make it possible to examine similarities in the genetic architecture of Finns and other European peoples. Use of the Atlas has revealed, for instance, that:

• Finns are unique on the genetic map of Europe; we differ considerably both from Central Europeans and from our neighbours to the east.

• Genetically, Finns have more in common with, for example, the Dutch or Russians living in the area of Murom, to the east of Moscow, than with our linguistic relations, the Hungarians; genetic closeness clearly follows geographic distance more closely than linguistic distance.

• Owing to our settlement history, the genetic differences among Finns are great on both the east/west and north/south axes; the greater the geographic distance is, the greater the genetic differences are. In comparing the Finnish dialect areas, the greatest genetic differences are found between Finns of Southwest Finland and inhabitants of Kuusamo in Northeast Finland.

• The linguistic link between Swedish-speaking Finns living in coastal areas and Swedes is also reflected in the greater genetic closeness of these two groups in comparison with Finnish speakers.

During 2010 the Finnish Gene Atlas will be supplemented with the first Finns whose whole genome will be fully sequenced.

Additional information: Senior Researcher Samuli Ripatti, Institute for Molecular Medicine Finland FIMM, tel. 020 610 8159 or samuli.ripatti@fimm.fi

GeneSapiens has become a widely-used resource for the international scientific community.

Kilpinen S, Autio R, Ojala K, Iljin K, Bucher E, Sara H, Pisto T, Saarela M, Skotheim RI, Björkman M, Mpindi JP, Haapa-Paananen S, Vainio P, Edgren H, Wolf M, Astola J, Nees M, Hautaniemi S, Kallioniemi O. Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues, Genome Biol. 2008; 9(9):R139. doi:10.1186/gb-2008-9-9-r139

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