As for the mechanisms in which these four genes intervene, they have no influence on the regulation of glutamate concentrations but on other processes. “The MEFD2 gene plays a role in the differentiation and survival of neurons.  TGFBR2 is also active in neuronal differentiation as well as in the proliferation of these cells, endothelial cells and extracellular matrix production”, Professor Schoenen underlines. “These genes therefore seem to be linked to the regulation of neuronal circuits and vascular functions. It’s a very interesting discovery because we already demonstrated many years ago that between attacks, the brain of a migraine sufferer is characterised by an abnormal functioning of some neuronal circuits.  Furthermore, vascular reactivity is disrupted in migraines”, he continues.

The function of the proteins coded by the genes LRP1 and TRPM8 is completely different. Both allow cells to interact with their environment, but in a different way. “TRPM8 codes for an ion channel activated by cold and menthol in the membrane of sensory nerve cells while LRP1 codes for a neuron and smooth muscle surface receptor allowing apolipoprotein E (APOE) to be captured and thus supply the cell with cholesterol", explains Jean Schoenen. The first one plays a role in the nociceptive system, i.e. the pain circuit, and in migraine, it is the pain receptors in the meninges that are involved. The second one is involved in the metabolism of neurons and vascular smooth muscle.  The genes responsible for migraine susceptibility are thus found there as well!

At the crossroads of multiple factors

“It’s important to mention that taken separately, the genetic variants identified up to now increase the risk of migraine by less than 20 % in carriers”, Jean Schoenen specifies. It is therefore highly likely that the majority of migraine sufferers have an accumulation of several susceptibility genes, with the migraine threshold depending on this accumulation. The more a person has genes making them susceptible to migraine, the more their migraine threshold is likely to be surpassed. This is when migraine attacks occur. “It’s like lighting the wick of a barrel of gunpowder. The genes fill the barrel with gunpowder and determine the length of the wick;  environmental factors light the wick”, the scientist explains.

The scorecard of the scientists in search of susceptibility genes involved in this polygenic disorder is therefore far from being complete. Moreover, the environmental and epigenetic influences that participate in the occurrence of migraine are still not properly understood. “Given that women are more affected by migraine than men, it could be, for instance, that the variations in ovarian hormones which are known to trigger attacks, modify the functioning of some of the genes involved in migraines, but this still needs to be demonstrated", emphasises Jean Schoenen.

While there is still a long way to go before winning the war against migraine, the discovery of every new susceptibility gene is a battle won. And every one of these battles brings us closer to the day when a more effective treatment against migraine will appear, to the benefit of at least 20% of our fellow beings.