A study of 150 Danish families with migraine shows that the disorder often results from variation in the genes related to how the brain manages serotonin.
Millions of people worldwide have migraine headaches, and yet researchers have not yet fully understood this disorder or its causes.
Danish researchers have now dug a little deeper to understand migraine and have found that people with migraine often have substantial variations in the genes that develop the serotonin-related receptors and signalling pathways.
Serotonin is a multifunctional neurotransmitter that regulates sleep, appetite and memory. It influences the feeling of well-being and joy and can affect the development of depression.
The discovery that serotonin is involved in migraine is new but does not come as a huge surprise to one researcher behind the new study.
“The serotonin receptor is interesting because many drugs target that receptor. We can also therefore say that our discovery is not an a-ha experience, but it makes sense in the context of what we have done,” says Thomas Folkmann Hansen, Associate Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen and Senior Research Manager, Danish Headache Center, Rigshospitalet, Glostrup, Denmark.
The study was recently published in Brain.
Different parts of the brain play a role in migraine
Two parts of the brain and the blood vessels are primarily involved when people have migraine: the trigeminal nerve, the visual cortex in the back of the head and the aorta.
The trigeminal nerve is involved in the two main types of migraine: migraine with aura and migraine without aura.
The difference between the two types of migraine is that people with migraine with aura experience various sensory disturbances, and 95% experience temporary visual disturbances that disappear again.
In the new study, the researchers investigated whether variation in the genes behind the trigeminal nerve, visual cortex and aorta are especially expressed among people with migraine.
Examined genomes from thousands of people with migraine
In the study, the researchers performed whole-genome sequencing of the DNA of 874 people from 117 families in which migraine was clearly inherited for several generations.
The researchers also collected data from an additional 1,930 people with migraine and 1,000 controls without migraine. The purpose was to determine whether they could replicate the results they had found in the families.
The researchers compared the genomes of the migraine-affected individuals with the genomes of the controls and found that migraine was often associated with high variation in the genes in the trigeminal nerve that are associated with the serotonin receptor and serotonin signalling pathways.
This means that individuals with migraine appeared to have accumulated many more mutations in precisely these genes.
“Genetic variants accumulate, and this seems to affect serotonin signalling in a direction that is related to the development of migraine,” says Thomas Folkmann Hansen.
No association with the blood vessels
Thomas Folkmann Hansen says that most of the people involved in the study had migraine with aura.
The results are therefore interesting since they contribute to the debate on the reason why people develop migraine with aura.
Researchers have generally been divided into two camps: those who claim that the brain causes migraine and those who claim the blood vessels that supply the various parts of the brain with oxygen and nutrients cause migraine.
In the study, the researchers found no accumulation of variants in the genes related to blood vessels.
“We may not be able to refute the hypothesis that the blood vessels play a role, but our results indicate that the brain is important in developing migraine with aura,” says Thomas Folkmann Hansen.
The number of variants is the smoking gun
Thomas Folkmann Hansen says that the study can help pave the way for further research into the genetic causes of migraine.
Indeed, some of the genetic variants involved appear to be common, whereas others appear to be rare.
Although the results cannot determine the individual significance of individual genetic variants for the risk of developing migraine, the research suggests which genes are especially affected when people have migraine.
“We wanted to find the migraine gene, but we did not. But we identified genes that appear to contain many mutations, which can change the functionality of the gene and thereby contribute to developing migraine. The number of variants seems to make things go wrong and not just the presence of an individual variant in an individual gene,” says Thomas Folkmann Hansen.
“Functional gene networks reveal distinct mechanisms segregating in migraine families” has been published in Brain. Co-author Thomas Folkmann Hansen is an Associate Professor at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen and Senior Research Manager, Danish Headache Center, Rigshospitalet, Glostrup, Denmark.