Largest-ever family study of migraines provides new insight into the disease

A new study found that many common genetic variants — each with a small effect — together explain why migraines cluster in some families.

The study, lead by scientists from Massachusetts General Hospital, Harvard Medical School, the Broad Institute and the University of Helsinki, investigated three subtypes of migraines using data from about 1,500 Finnish families. It is the largest ever study of families with migraine. 23andMe was one of more than a dozen institutions that contributed to this study.

“Both rare, high-impact and common genetic variants with smaller impact could contribute to the familial aggregation of migraine,” said Padhraig Gormley, Ph.D, a lead author of the study who works at the Broad Institute. “In this study, we wanted to find out which one is more important and whether the genetic load is higher in certain types of migraine.”

Migraines — the severe recurring headaches that may include symptoms such as nausea and light sensitivity — are fairly common, affecting an estimated 20 percent of the population. About a third of those with migraines experience additional neurological symptoms, referred to as aura, which occur just before or during a migraine. This study wanted to see if there were different genetic mechanisms involved in two subtypes of migraines with aura: migraines with typical visual aura, and the less common hemiplegic migraines, which are accompanied by a motor weakness aura.

While scientists have previously identified genetic variants associated with this common brain disorder, there is still much to learn about the underlying biology. One lingering question is why the condition clusters in families, and that’s what this study focused on.

Two years ago this same consortium of scientists conducted what was at that time the largest genome-wide association study of migraines ever done. That study found more than 40 genetic variants associated with the condition.

For this most recent study, the researchers wanted to determine if rare variants or a combination of rare and common variants could explain why migraines cluster in some families. As in the last study, this one relied in part on a meta-analysis of data gathered together from 22 different genome-wide association studies. Together this included data from more than 375,000 people, and about 170,000 of those individuals are 23andMe customers who consented to participate in research.

By using this data, the researchers were able to create something called a “polygenic risk score,” gathering together all the variants that contributed to risk for migraines identified in these studies. This model was then used in studying a smaller cohort of Finnish families with migraines. The scientists were interested in seeing if there was a difference in comparing the genetic risk within families to risk for migraines in the general population, as well as looking to see if these differences could be explained by the accumulation of common variants or the contribution of a few rare variants. They were particularly interested in looking at hemiplegic aura migraines, which were thought to be caused by rare genetic variants in three genes.

But what the researchers found across the board was that the combined effect of common variants was greater than the effect of any rare variants.

“Our study supports the hypothesis that migraine subtypes are genetically heterogeneous diseases, and that common polygenic variation significantly contributes to the aggregation of the disease in families, both for common and rare migraine subtypes”, said Aarno Palotie, Ph.D, another study author who works at the University of Helsinki.

The study was conducted in collaboration with members of the International Headache Genetics Consortium and the 23andMe Research Team.

Read more on the study in the publication Cell.