Discovery of 44 rare genetic variants could lead to treatments

According to Gyda Bjornsdottir, PhD, research scientist at deCODE Genetics and lead author of this study, although most studies on the genetics of migraine have focused on migraine as a single disease, several genetic associations have been found in migraine that are informative.

“The latest article on the genetics of migraine associated more than 120 common genetic variants with migraines,” said Bjornsdottir Medical News Today. “They are in different genes, with different functions, coding for different proteins.”

“We now had the resources and number of whole-genome sequenced individuals to study rare migraine-associated variants and focus on migraine subtypes with and without aura,” she added. “There is evidence that these are perhaps different pathologies to some extent – ​​different biologies behind these migraine subtypes.”

Kari Stefansson, CEO and co-founder of deCODE Genetics, said Medical News Today The research results provide new evidence that migraines with and without aura are two distinct conditions.

“Migraine patients present in two ways – they present as patients who have an aura and then as people who simply have a headache without any preceding events,” Stefansson said. “These are clinically very different things.”

“What Dr. Bjornsdottir did with her work was demonstrate to us that this difference is not just a difference in patients’ perception, it is biologically based,” he added. “She showed unequivocally that although there is overlap between the pathogenesis of these two forms of migraine, the two are clearly very distinct.”

For this study, Bjornsdottir and his team analyzed genetic data from more than 1.3 million participants in genome-wide association studies, 80,000 of whom had migraines.

Focusing on genetic sequence variants associated with migraines with and without aura, researchers discovered associations with 44 rare variants, 12 of which are new.

One of these variants is the PRRT2 genewhich has been associated with a high risk of migraine with aura and also epilepsy.

“Both are neurological diseases to some extent,” Bjornsdottir said. “Both diseases arise in attacks of paroxysmal diseases that comes and goes. Both can have the aforementioned aura elements. We calculated the genetic correlation between these two diseases in our data. And we found that there is some genetic correlation, but they are not highly correlated. In fact, this variant appears to be quite unique in terms of affecting both epilepsy and migraine with aura in this biology that we have detected.”

Another rare variant found by researchers is the KCNK5 genewhich protects against severe migraines and brain aneurysms.

“Migraine has neurological and vascular etiologies,” explained Bjornsdottir. “Here we have a variant that is in a potassium channel gene that is expressed in both neurons and arteries. We may have evidence here of the biology that is common to migraine, both in terms of its neurological and vascular aspects, but we may also have a variant that can lead to severe headaches as a prequel to cerebral aneurysms.”

Stefansson said the more we understand about migraines, the more likely we are to find new ways to treat them.

“And we believe that with this study, Dr. Bjornsdottir has made a very significant contribution to our understanding of migraine,” he said. “So I think this will inevitably increase the likelihood of discovering a new treatment. And furthermore, the genes discovered encode proteins that are quite attractive as (therapeutic) targets.”

As for the next steps in this research, Stefansson said they will look at the differences between migraines in men and women.

“Dr. Bjornsdottir will do a sex-based analysis to see which genes cause migraines in men and which genes cause migraines in women,” he explained. “And this is important because we need to understand sexual differences.”

“There are considerable sex differences in migraine prevalence worldwide,” Bjornsdottir added. “We’re sure there are some biological explanations for this, but we don’t know what they are yet. So this is the next logical step to study.”

Medical News Today also spoke with Dr. Medhat Mikhael, a pain management specialist and medical director of the Spine Health Center’s nonoperative program at MemorialCare Orange Coast Medical Center in California, who was not involved in the study.

“It’s really an incredible study because it looks like they can detect some of the new genetic variants that can detect patients at high risk of developing migraines and link these variants to other possible serious diseases,” he said. “As with migraine with aura, some have linked it to brain diseases such as seizures, and others have misdiagnosed it as migraine and ended up with a brain aneurysm. This is… an incredible study because it could make a huge change in the field of migraine prevention and treatment.”

Mikhael said identifying these new genetic variants could help doctors with early diagnosis and prevention of migraines, as well as help prevent misdiagnoses of migraines with other serious neurological conditions.

As this study was carried out in a genetic laboratory in Iceland, Mikhael said he would like to see this research advanced to the point where it could be used to test people with migraines through easier and simpler tests.

“May the testing process move forward to where we can see this available in some accessible labs for patients covered by insurance,” he said. “So we can do not only early detection, early diagnosis, early prevention, and avoid misdiagnosis and avoid complications like a hemorrhagic aneurysm or stroke for a patient who has been misdiagnosed as migraine. Or you have a migraine with aura, but someone missed some of the underlying seizures and hemiplegias that can happen to this patient because they were detected early, prevented early, and treated early.”