Feature: Genetic headache

Those who suffer from migraine will know that it's more than just a headache. Besides intense head pain, many sufferers also experience visual and auditory disturbances of varying intensity, such as flashes of light or patterns along with photophobia or phonophobia - sensitivity to light and noise. Migraines can also be accompanied by nausea, tingling or numbness, speech disturbances and other debilitative effects to the point of resembling a minor stroke. The trigger for a migraine can be something as trivial as a change in lighting, a sound, the smell of strong perfume or even a change in barometric pressure.

The causes of migraine have long eluded researchers, although there have been tantalising clues as to its origins - such as that women are substantially more susceptible. This has led many to believe the disorder is linked to hormones - a link that is further borne out by the fact that the incidence of migraine is about equal between the sexes until puberty, when women being to experience migraine in greater numbers.

Another clue comes from evidence that migraine is clearly inherited: if one of your family members suffers from migraine, you're far more likely to also experience them as well. This indicates that migraine has a genetic component, but the trick was uncovering the gene or genes responsible.

It has been the mission of Professor Lyn Griffiths, Director of the Griffith Institute for Health and Medical Research at Griffith University in Queensland and her colleagues over the past 15 years to reveal these genes - and they've made some startling progress in uncovering some of the mysteries of migraine.

"When we began our research, most people felt there was probably one gene and it was probably inherited in a dominant way - meaning it occurs in every generation," she says. "It's now obvious from our studies that it's not a single gene disorder, there are multiple genes - different genes in different families, and different susceptibility variants occur in different individuals. So it's strongly genetic, but it's not one gene."

Griffiths has now identified three genetic regions that are associated with susceptibility to migraine, suggesting it might be a more complex disorder than first thought. She hopes that by revealing the genes involved and how they affect various aspects of brain function, we can not only gain a better understanding of migraine but also develop more accurate diagnostic tools and even more effective targeted treatments.

Mutiny and migraines

Griffiths' early investigations into migraine in the late 1990s looked at large multigenerational Australian families and tracked the genes through the families that were responsible for susceptibility to migraine. But there's only so large that genetically related families get in the broader Australian population.

So in 2000 Griffiths and her team, looking to delve deeper into the genetic underpinnings of migraine as well as cardiovascular disease, moved on to a examine a new population, one with quite unique properties for her purposes: the population on Norfolk Island. This small island, lying 3,400 kilometres off the coast of Australia in the middle of the expansive blue of the Pacific Ocean is home to a little over 2,000 people.

But what's remarkable about them is that around 70 per cent are descendent from only 21 individuals: the nine mutineers from the Bounty and the 12 Tahitian women they brought with them to their original home of Pitcairn Island in 1790. "It's a lovely population. It's isolated. It's what's called a founder effect population." This means that after many generations the genetic variation within the population is significantly reduced, making them ideal when it comes to isolating the genetic bases of hereditary disorders like cardiovascular disease or migraine.

In 2000, Griffiths and her colleagues set up a clinic on Norfolk Island, performing full health checks for anyone willing to be involved in the study. About two thirds of adults were happy to participate, also venturing DNA samples. And what Griffiths found from them was well worth the trip.

"We found a very high prevalence of migraine," she says. "You wouldn't expect that. In Australia overall it's about 12 per cent. There it's 27 per cent."

This made the population of Norfolk Island ideal for uncovering the genes that underlie the disorder. "We did a full genome scan looking for regular markers across all of the chromosomes in that population. Then we tried to track down the location of genes that play a role in these traits. We've identified a new genomic region for migraine and six for cardiovascular risk trait regions."

That's a huge step forward, but it's not the end of the story. "We have regions - we know where they are in the chromosome - but at this stage there are many genes in those regions. What we're currently doing is undertaking fine mapping and sequencing of genes within these implicated regions."

That's not to say they know nothing about what genes play a role in migraine. Their studies to date have implicated three classes of genes. The first deals with neurotransmitters, affecting things like calcium channel genes in brain neurons as well as levels of dopamine and serotonin.

The second influences hormones. "That makes a lot of sense," says Griffiths, referring to the fact that migraine affects three times more women than men. "It was pretty obvious that hormones play a role, but it took us a while to work out that we should look at the genes that relate to hormones - and that's the hormone receptor genes. What we found was that there were variations in both oestrogen and progesterone receptor genes that make people more susceptible to developing migraine. If you have both variants you are even more susceptible. We think that's why more females suffer from migraine and why fluctuating hormone levels that interact with these gene variations can trigger the attacks."

The third class of genes relates to blood flow and vascular differences, which raises an intriguing link between migraine and another more severe disorder, stroke. "For people who suffer from migraine with aura, they not only experience the head pain, nausea, vomiting, photophobia and phonophobia, but they also have neurological disturbances either just before or in the early stages of it. Some of those symptoms tend to overlap with stroke type symptoms." These can include tingling, numbness, speech disturbance and even numbness in parts of the face.

"It can be hard to differentiate the symptoms between migraine with aura and stroke. Also, people who suffer from migraine with aura tend to show a higher co-morbidity with stroke. There seems to be some genetic overlap."

Griffiths believes what the two have in common could be a functional mutation in a gene that affects levels of the enzyme methylene tetrahydrofolate reductase (MTR). "If you have the mutation, it results in high levels of homocysteine, and high levels have been found to increase risk for cardiovascular disease and stroke. We tested for this mutation in migraine with aura and found it was a predisposing factor for migraine with aura. We think it's a gene that links these two conditions."

The identification of MTHFR and homocysteine as playing role in migraine raised the tantalising possibility of a new, and inexpensive, treatment. "It's been known for quite some time that you can drop homocysteine levels down to normal by increasing the amount of folate and vitamin B in the diet." So Griffiths embarked on a trial to see if such a rudimentary treatment might have an effect on migraine sufferers. It did. "It had a very significant impact on their migraines, reducing the severity, frequency and the disability from the disorder."

Griffiths is currently embarking on a larger trial to determine whether there's a difference in response to vitamin B and folate depending on whether the individual has one or two mutations in the MTHFR gene. If so, then doses might need to differ slightly to get the maximum effect.

"We know there are multiple genes involved in migraine, so it makes sense that not every person is going to respond to the same treatment in the same way. It's more important to start to target treatment to the actual gene, and we've undertaken the first pharmacogenetic trial that has actually attempted to do just that, to come up with a treatment targeting a specific gene that affects around 19 per cent of migraine sufferers. I think we're going to start seeing this more often, not just in migraines, but in other disorders. If you can define the genes, you can come up with new treatments, and these new treatments are going to be much more personalised and targeted and more effective."

The hunt continues

Where to next? The hunt for the genes underlying migraine is not over yet. "We know, for example, that in the hormone area there are two genes. We don't think there's likely to be many more. In the vascular or blood flow are there have been two identified now, but there may be others there. Then the neurotransmitter regions, there are three definite genes as well as a susceptibility gene, so there's four at this stage, but I still think there's at least one or two others in that area."

"In fact, we have mapped a gene to the X chromosome that seems to be playing a role in quite a number of families, and we expect that one is neurotransmitter gene. It's still hard to say how many there are at this stage."

Griffiths' research is not only revealing insights into the causes of migraine, but how certain aspects of the brain function go wrong when a migraine occurs. Her findings on neurotransmitter and hormone genes seems to reinforce the theory that migraine sufferers have 'hypersensitive' neurons that leads them to respond far more strongly to changes in their environment. "I like the hypersensitivity theory, but I don't know if it's true."

Currently, Griffiths and her team have funding from the NMHRC to continue their studies on Norfolk island, this time delving deeper into the genes involved in migraine and cardiovascular disease by taking RNA samples and exploring gene expression. She's also involved in other studies with the Norfolk Island population, looking at things like the genetics of glaucoma and bone density, so the founder population there might still have many secrets yet to reveal