The largest genome-wide association study so far reveals new variants associated with migraine risk, including variants linked to specific migraine subtypes.
Are the two main subtypes of migraine – migraine with aura and migraine without aura – different disorders, and if so, do they have unique underlying causes? Is migraine a neuronal disorder, a vascular disorder, or both? The largest genome-wide association study (GWAS) in the migraine field to date now adds to the debate over these age-old questions.
Researchers from the University of Helsinki in Finland report 123 genetic variants associated with migraine, including 86 that had not been identified in any previous studies.
Importantly, the authors found a handful of variants specific to migraine with aura or to migraine without aura, as well as variants in genes expressed in both vascular and central nervous system tissues. Of the new migraine-associated variants, several were observed in genes for migraine-specific drug targets, including calcitonin gene-related peptide (CGRP) and the serotonin 1F receptor.
“This important study is the largest and most recent genome-wide association study to identify variants associated with susceptibility to migraine,” said William Renthal, of Brigham and Women’s Hospital and Harvard Medical School in Boston.
“We know there is a genetic component to migraine, and this study identifies several avenues for future research to dissect how an individual’s genetics contributes to their risk for migraine,” added Renthal, a neuroscience and genetics researcher as well as a headache clinician who was not involved in the current research.
The study was published in the February 2022 issue of Nature Genetics.
100,000 people with migraine, hundreds of genetic markers
In a GWAS, researchers scan the genome – a person’s complete set of genetic information – to uncover genetic variants associated with disease. Interested in identifying variants associated specifically with migraine, first author Heidi Hautakangas and colleagues used genomic data from five existing migraine study collections, including the 2016 International Headache Genetics Consortium, 23andMe, the UK Biobank, the GeneRISK study, and the Nord-Trøndelag Health Study.
Pooling the five studies gave the researchers genomic data for 102,084 people with migraine and 771,257 control subjects. All individuals were of European ancestry.
The GWAS revealed 123 genetic variants associated with migraine, including 86 that had not previously been linked to migraine. That so many variants turned up was no surprise to Mikko Kallela, a neurologist at Helsinki University Hospital and a co-author on the study.
“When I started studying the genetics of migraine in the 1990s, we were naïve and thought there would only be a handful of genes that contributed to migraine. Now, this study completely blows that idea up. You have over a hundred genes and counting. The final number isn’t important, because more genes will be identified with larger and larger studies, but it represents the complexity of the genetics underpinning migraine.”
New insight into an old question
More information from genetic studies can enhance the understanding of disease in many ways, and in the current instance, the authors were particularly interested in wading into some decades-long debates about the pathophysiology of migraine.
First, researchers and clinicians have long contemplated whether the two main migraine subtypes – migraine with aura and migraine without aura – are separate disorders or a single condition at various stages along a spectrum of severity.
“We know there are differences between migraine with and without aura from a clinical perspective. But previous genetic studies were underpowered to look specifically at migraine with aura, as this subtype is less common compared to migraine without aura,” explained Renthal.
The GWAS identified three genetic variants specific to migraine with aura, including variants in genes called HMOX2, MPPED2, and CACNA1A. The CACNA1A gene, which belongs to a family of genes that encode ion channels through which calcium flows across the cell membrane, had previously been linked to familial hemiplegic migraine, a rare subtype of migraine with aura. The researchers also discovered two genetic variants specific to migraine without aura, near genes called SPINK2 and FECH.
An additional nine variants were found to increase migraine susceptibility regardless of the subtype. This finding supports the idea that the two migraine subtypes have some common genetic underpinnings.
The importance of determining the genetic mechanisms underlying migraine with aura and migraine without aura is understated, according to Kallela.
“There aren’t effective treatments for the migraine aura. But it tends to come and go, so it’s usually not the big problem. However, it is important to understand the differences between the two subtypes, because patients with the aura have an increased risk of strokes compared to migraine without the aura,” Kallela said.
Vascular or neurological?
The new GWAS also enters into a second long-running debate in the field: Is migraine a vascular disorder, a neurological disorder, or both?
“A previous GWAS identified an increase in genetic markers expressed in vascular and smooth muscle tissues, which suggested the vascular component played a larger role in causing migraine,” Renthal recalled. “This caused quite a stir amongst the headache community, which had been focused on neurological contributions to migraine over the previous decade.”
In the current study, the investigators looked at gene expression (which genes are “turned on”) and other data from multiple tissues, to determine whether migraine-associated variants were enriched in specific tissues or cell types. Consistent with previous findings, the authors found enrichment in cardiovascular tissues/cell types, including the aorta, tibial artery, and coronary artery, but also in central nervous system tissues such as the prefrontal cortex and basal ganglia.
“This is a basic but important finding. It’s not only the blood vessels or the central nervous system that contribute to migraine; it’s both,” Kallela said.
On the right treatment path
One area of agreement in the field is the need for more effective migraine treatments. Triptans, which target serotonin 1B and 1D receptors, have been used since the 1990s. More recently, ditans, which target the serotonin 1F receptor, and gepants, which antagonize the CGRP receptor, have emerged. However, there are still many people with migraine who do not respond to currently available treatments.
The GWAS identified new risk variants within genes that encode these well-recognized targets for migraine drugs, suggesting that drug development in the field has generally been on course. For instance, one variant was in the CALCA/CALCB genes, which encode CGRP itself. Another variant was in the HTR1F gene, which encodes the serotonin 1F receptor.
“It was remarkable that there were genetic markers in the same genes that the medications target,” Kallela said. “It means the treatments were on the right track to begin with.”
The authors note in their paper that their findings could potentially help lead to the identification of new drug targets.
In the meantime, Renthal is excited about the research possibilities the treatment-related findings offer.
“Do the people with variants in CGRP or HTR1F respond differently to medications that target these genes? This new GWAS provides a great platform to further investigate the treatment response between various groups of patients.”
Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on Twitter @lincolntracy.
Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Hautakangas et al. Nat Genet. 2022 Feb;54(2):152-160.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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