Griffith team pinpoints genetic clue to migraine

Researchers at Griffith University's Genomics Research Centre have found an important clue to the cause of hormonally induced migraines, that may explain why women are three times more likely than men to suffer from migraine.

Prof Lyn Griffiths and her PhD student Natalie Colson have found a strong association between hormonal migraine -- also known as 'menstrual' migraine -- and a subtle variation in the gene for the alpha oestrogen receptor, on chromosome 6.

The susceptibility gene has a single nucleotide polymorphism (SNP) in codon 6.

Colson said the SNP was a so-called synonymous polymorphism -- it does not alter the amino-acid sequence of the receptor protein, indicating that hormonal migraines are not caused by changes in the configuration and function of the receptor.

For this reason, Griffiths and Colson suspect the SNP may not itself be causal in hormonal migraine, but is a marker for another polymorphism in non-coding DNA near the gene, that alters the way the gene is expressed in particular tissues, including the brain.

If so, hormonal migraines may result from fluctuations in the number of oestrogen receptors in neural tissue, as oestrogen levels change with the menstrual cycle.

Colson said oestrogen receptor activity in turn modulates neurotransmitter activity -- particularly serotonin, the brain's natural calmative.

The Griffith team's discovery may help resolve a long-standing mystery about the association between serotonin disturbances and migraine.

'Miracle' migraine drugs like sumatriptan and zolmitriptan, which can quell a severe migraine within less than 15 minutes, modulate serotonin activity. But researchers have been unable to link inherited polymorphisms in serotonin receptor genes with increased susceptibility to migraine -- the serotonin disturbances are thought to originate in the activity of other, as yet unidentified genes whose activity links into the serotonin system.

Griffiths and Colson have now implicated the alpha oestrogen receptor as a suspect in this 'action-at-a-distance'.

Likely suspects

Griffiths has previously used family-pedigree studies to identify three genetic loci associated with susceptibility to migraine, on chromosomes 1 and 19, and on the X chromosome. The culprit genes have yet to be identified.

But their genome scans failed to detect any susceptibility locus on chromosome 6, so Griffith took an alternative approach: she went looking for likely suspects among genes involved in the oestrogen system, zeroing on the alpha and beta oestrogen receptor genes.

They took DNA samples from 300 patients, and 300 controls -- most of the 300 patients were women who suffered regularly from menstrual migraines, but there were some males among them. Oestrogen, like testosterone, is a 'unisex' hormone.

Many females begin to suffer migraine with the surge in oestrogen levels at puberty. Males produce much lower levels of oestrogen than females, and in the absence of a menstrual cycle. Although their oestrogen levels do not fluctuate markedly, they are potentially susceptible to hormonal migraines associated with abnormal expression of the oestrogen receptors in the brain.

Griffiths and Colson have confirmed that the same polymorphism responsible for menstrual migraines in women is associated with a susceptibility to migraine in some males.

Griffiths said that changed oestrogen levels during pregnancy and menopause can also affect women's susceptibility to migraine -- so the contraceptive pill and hormone replacement therapy may increase susceptibility to migraines, or worsen their severity.

They have published a paper describing their discovery in the May edition of Neurogenetics.