Migraine and Genetics: Largest study to date gives new clues

• A multinational study that trawled the genomes of more than 100,000 people has trebled the tally of known genetic risk factors for migraine.
• The study found that two types of migraine — with or without aura — have distinct genetics but also share some genetic characteristics.
• The genetic regions that the study identified could provide new leads for the development of drugs that target the symptoms of different types of migraine.

Migraine is a condition that causes a pulsating or throbbing headache, usually on one side of the head. The headache often accompanies other symptoms, such as nausea, hypersensitivity to light and sound, and vomiting.

A single episode can last several days, with severe cases affecting a person’s ability to work or study.

More than 1 billion people worldwide experience migraine headaches. Globally, migraine is the second most disabling medical condition, after lower back pain, in terms of years lived with disability.

The condition is about three times as common in women as it is in men.

“Migraine is the most prevalent and one of the most disabling neurological diseases in the world,” Dr. Roger Cady, a board member of the National Headache Foundation in Chicago, told Medical News Today. Dr. Cady was not involved with the study.

“Yet, it is highly heterogeneous with even the best acute and preventive treatments, leaving a significant number of patients without enduring treatment success,” he continued.

There are drugs to treat the headaches themselves and others to prevent them. However, they are far from perfect and do not work for everyone.

The exact cause of migraine is unknown, but according to the leading theory, it is a neurovascular condition that involves an interaction between the blood vessels in the head and the brain itself.

Research suggests that genes account for up to 60% of a person’s risk of having the condition.

Almost one-third of all people with migraines experience auras. These are sensory symptoms, such as flashing lights, that occur before or during a headache.

However, whether the two main subtypes of migraine — with aura (MA) or without aura (MO) — are genetically distinct conditions has been a controversial topic.

Trebling of genetic risk factors

Researchers have now conducted the largest genetic study of migraine to date, which involved analyzing the genomes of 102,084 people with migraine and those of 771,257 controls who do not have the condition.

They identified 123 genetic regions, or loci, that are associated with the condition — 86 of which were previously unknown. This represents a trebling of the known genetic risk factors.

They also discovered three genetic loci that appear to be specific to MA, two that are specific to MO, and nine that are associated with both types.

“In addition to implicating tens of new regions of the genome for more targeted investigation, our study provides the first meaningful opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes,” says first author Heidi Hautakangas, Ph.D., from the Institute for Molecular Medicine Finland at the University of Helsinki.

Matti Pirinen, Ph.D., who is an associate professor of statistics at the University of Helsinki in Finland and led one of the research groups that performed the study, spoke with MNT about the findings:

“Based on our results, it seems that most genetic risk factors are shared between MO and MA, but we also observed a few genetic variants that confer risk only for MA or only for MO, which shows that there are also some genetic differences between these two subtypes of migraine. Genetic risk factors of a particular subtype of the disease can be important clues for future development of more effective drugs against that subtype of the disease.”

The study has been published in Nature Genetics.

New clues for developing treatment

The researchers identified two regions that contain genes that recently developed migraine drugs target.

The first region contains genes that make a protein called calcitonin gene-related peptide (CGRP), while the second region contains a gene that makes a receptor called the serotonin 1F receptor. This receptor binds to the neurotransmitter serotonin.

A new class of treatments called CGRP inhibitors, or gepants, blocks the first gene, and a new class of migraine drugs called ditans stimulates the serotonin F1 receptor.

“This too is encouraging and suggests that through further definition and understanding [of] these risk loci, new highly specific drug targets may be discovered having efficacy as both acute and preventive treatment of migraine,” said Dr. Cady.

In theory, genetic data could help identify targets for drugs to alleviate particular symptoms, such as aura, for which there is currently no treatment.

Dr. Cady said that the study “offers hope of a new era for improved understanding of migraine pathophysiology and development of more targeted, personalized pharmacological treatment.”

The International Headache Genetics Consortium, which brings together migraine research groups in Europe, Australia, and the United States, carried out the genome-wide association study.

Genome-wide association studies pool data from the complete genomes of thousands of people who have a particular disease. They compare them with the genomes of controls who do not have the condition to identify its associated genetic variations.

In particular, the studies can pinpoint genetic changes that are linked to particular phenotypes, or manifestations of the disease, such as aura in migraine.

“One can only assume many other migraine phenotypes and perhaps migraine comorbidities, such as anxiety, depression, and other pain disorders, will become more clearly defined and treatable using this methodology in the future,” said Dr. Cady.

In addition to providing genetic information about subtypes of the condition, the study also confirmed that a combination of neural and vascular (blood vessel) changes causes migraine.

In their paper, the authors write:

“Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.”

Limitations of the study

The authors note some limitations of their study. For example, they note that most migraine diagnoses are self-reported.

“Therefore, we cannot rule out misdiagnosis, such as, for example, tension headache being reported as migraine, which could overemphasize genetic factors related to general pain mechanisms and not migraine per se,” they write.

In addition, they say that even larger sample sizes will be necessary to get a more accurate picture of the genetic similarities and differences between different types of migraine.

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