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GWAS Uncovers Risk Loci Linked to Most Common Type of Migraine

NEW YORK (GenomeWeb News) – Members of the International Headache Genetics Consortium have identified new genetic loci associated with the risk of migraine without aura, the most common form of migraine headache. Among them are sites containing genes involved in brain blood flow and transmission across synapses in the brain.

"The identified genes open new doors to investigate how this type of migraine comes about," co-corresponding author Arn van den Maagdenberg, a human genetics and neurology researcher at Leiden University Medical Centre, said in a statement.

As they reported online yesterday in Nature Genetics, he and his colleagues did a genome-wide association and validation study involving thousands of German and Dutch individuals who did or did not experience migraine without aura. The search led to two new migraine-associated loci on in and around the chromosome 1 gene MEF2D and the chromosome 3 gene TGFBR2.

In the process, the team also verified previously detected associations between migraine risk and sites near two other genes, TRPM8 and LRP1, and uncovered more tenuous ties to SNPs in two more genes, PHACTR1 and ASTN2.

"This study identifies the first susceptibility loci for migraine without aura," the study's authors noted, "thereby expanding our knowledge of this debilitating neurological disorder."

Migraines are severe headaches affecting one side of the head that are accompanied by symptoms such as nausea, vomiting, and an aversion to light and sound, they explained. A minority of those affected by the neurovascular condition also experience so-called "aura" symptoms, sensory perceptions that precede the onset of a headache.

A 2010 study by researchers involved in the International Headache Genetics Consortium uncovered a migraine-associated site on chromosome 8 site that was more closely tied to forms of the condition that included these aura symptoms.

Meanwhile, the group's more recent study of participants from the Women's Genome Health Study pointed to sites in and around three genes at other sites in the genome that were significantly associated with migraines with and without aura.

For the current study, the team decided to focus on individuals who had migraine without aura, which includes at least two-thirds of migraine patients. In the discovery stage of the study, collaborators from Germany and the UK used Illumina SNP arrays to genotype 1,208 German and 1,118 Dutch individuals with migraines, respectively.

Patterns in the genome were compared with those found in 2,564 unaffected individuals from the German cohort and in 2,016 unaffected controls from the group enrolled in the Netherlands.

From candidate SNPs identified in the GWAS, the team narrowed in on 18 variants at a dozen loci to take forward for validation testing in thousands more individuals with or without migraines from four European cohorts. They also tested SNPs at all four of the sites previously implicated in migraine risk in these cohorts, which together consisted of 2,508 cases and 2,652 controls.

The strongest migraine-associations that remained after this replication step included known loci on chromosomes 2 and 12, near the TRPM8 and LRP1, as well as two newly identified sites.

The latter included variants in the chromosome 1 gene MEF2D, which codes for a highly expressed transcription factor in the brain that's believed to govern processes related to neuronal differentiation and neuronal excitation, along with SNPs near TGFBR2 on chromosome 3 gene, which codes for a protein that helps regulate cell proliferation and differentiation.

The researchers saw two more suggestive associations as well, these involving variants near PHACTR1, a phosphatase and actin regulator-coding gene whose functions include some related to synaptic morphology and function, and ASTN2, an atroactin gene believed to influence brain development.

All but one of the six significantly associated or suggestive loci found in the analyses of individuals who had migraine without aura were also linked to forms of migraine that included aura symptoms in the team's follow-up in silico testing.

On the other hand, researchers explained, the chromosome 8 locus that was more strongly implicated in migraine with aura in the consortium's 2010 study did not turn up in the latest study, hinting that the MTDH gene at that site may contribute to aura-specific migraine risk.