Meta-analysis of the genetics behind migraine provides new understanding

Breaking new ground 3. dec 2023 3 min Associate Professor Thomas Folkmann Hansen Written by Kristian Sjøgren

Researchers have identified 44 genetic variants that influence the development of migraine. A researcher involved in the study says that these can be used diagnostically to determine the subtype of migraine and to identify the optimal treatments.

Migraine is an overarching term for several subtypes of this neurovascular disease. Some people have migraine with aura and experience sensory and visual disturbances; others just have a pounding headache.

The subtypes of migraine arise from different genetic underpinnings researchers have now identified.

In a meta-analysis, researchers identified 44 genetic variants associated with migraine, with small changes in specific genes increasing the risk of developing migraine.

By examining the genes in which the variants are located, researchers have now learned more about why migraine occurs, how migraine manifests itself and how people might be treated more individually.

The research has been published in Nature Genetics.

“This is the largest and most in-depth analysis of the genetics underpinning migraine and provides new understanding that may be clinically relevant in several ways, from developing new drugs to more specific individual diagnosis,” explains a researcher behind the study, Thomas Folkmann Hansen, Associate Professor, Danish Headache Center, Rigshospitalet, Copenhagen.

Data from thousands of people

The researchers used data on almost 650,000 people from data sets from Iceland (deCODE Genetics) and Denmark (Copenhagen Hospital Biobank and the Danish Blood Donor Study).

The researchers had access to genetic profiles of all the participants, and for most they also determined whether they had been diagnosed with migraine.

Many participants had also answered questionnaires on symptoms of migraine with or without aura but also on aura without migraine.

Based on the data, the researchers identified genetic variants that are associated with the risk of developing migraine and with the type of migraine.

“We previously identified some genetic variants against which antibodies have now been developed. They are now offered as preventive treatment and appear to be effective for people with migraine without aura. We hope that with this study we can identify several promising genes that can be used to develop new treatments for people with different subtypes of migraine, because the treatments for people with migraine with aura are not currently optimal,” says Thomas Folkmann Hansen.

44 new genetic variants

Some of the 44 genetic variants by the researchers are associated with increasing the risk of migraine with aura and others with increasing the risk of migraine without aura.

Different subtypes of migraine have long been known to result in different physical manifestations. Migraine with aura is characterised by depolarisation of the cerebral cortex during a migraine attack. This has a decisive role in the sensory disturbances expressed as aura.

Conversely, migraine without aura is more closely related to blood pressure and heart rate, and effective remedies for migraine without aura include blood pressure–lowering drugs.

“This is the first time that we have obtained such an accurate overview of which genetic variants influence migraine – with or without aura. Our study very clearly found that the migraine-associated genetic variants associated with migraine with aura are mainly present in the brain, whereas those associated with migraine without aura are mainly in genes within the smooth muscle around blood vessels and genes affecting heart rate and blood pressure,” explains Thomas Folkmann Hansen, who adds that the researchers are excited that they are now at a point where they can see which genes are specifically associated with migraine, with and without aura – insight which they did not have previously.

“This means that we are getting closer to understanding which genetic variants cause the visual disturbance in migraine and which cause the headache. We also found that some people only had visual disturbances but not migraine, and this strengthens our understanding that the genes for migraine and aura are separate,” he says.

Genetic variants also associated with other diseases

The researchers also identified other genetic variants that are quite useful in understanding migraine. One is almost exclusively present in one family in Iceland and is virtually synonymous with developing migraine, whereas other genetic variants only slightly increase the risk.

In addition, this genetic variant is also associated with an increased risk of developing Parkinson’s disease.

The researchers also found that another genetic variant was associated with an increased risk of developing migraine, and it was also associated with developing epilepsy.

Thomas Folkmann Hansen imagines that one type of mutation in this gene destroys some of the function, leading to migraine, whereas another type completely collapses the gene, and then it can be expressed as epilepsy.

“The research associates migraine with epilepsy in a new way. We hope that the existing treatments for people with epilepsy can be slightly modified and thereby improve migraine,” adds Thomas Folkmann Hansen.

Avenues for potential treatment

Thomas Folkmann Hansen imagines that the new knowledge could be relevant in both clinical and research settings.

A blood sample from people with migraine will probably provide relevant information about their subtype based on the genetic variants identified.

This study may also influence individual treatment. People with migraine without aura have good treatment options but not those who have migraine with aura.

However, analysing genetic variants can rapidly begin to determine whether a specific treatment will work for an individual, who can then receive treatment so that the doctors can focus more on the people for whom good treatments are not yet available. These are the treatments that the new study can help to promote.

Categorising people with migraine may be relevant in various clinical studies to investigate new treatments for people with migraine with aura.

The study also found genetic variants in many genes that could influence developing migraine and can therefore be promising drug candidates for future development.

“We are obtaining greater insight into improving treatment for the large subgroups of people with migraine with or without aura but also into how to treat the rarer forms of migraine, including with modified drugs that were originally developed for Parkinson’s or epilepsy,” concludes Thomas Folkmann Hansen.

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