GWAS Identifies Novel Migraine Risk Factors, Underscores Role of Neurovascular Mechanisms

Findings of the largest genome-wide association study conducted among migraineurs to date revealed novel risk factors for the condition, stratified by aura presence.

A genome-wide association study (GWAS) meta-analysis published in Nature Genetics identified 123 risk loci and subtype-specific risk alleles among 102,084 migraine cases—findings that unequivocally support neurovascular mechanisms underline migraine pathophysiology, authors wrote.

A total of 771,257 controls were included in the GWAS, making it the largest study of its kind. All individuals were of European ancestry.

Migraine can be categorized into 2 types: migraine with aura (MA) and migraine without aura (MO). Around one-third of migraineurs will experience an aura phase.

Previously, a GWAS that included 59,674 cases and 316,078 controls identified 38 genomic loci that confer migraine risk, while additional smaller GWAS have suggested additional loci exist.

In the current meta-analysis, researchers from the International Headache Genetics Consortium added 42,410 new migraine cases to the previously mentioned GWAS, increasing the number of migraine cases by 71%.

They also “assessed the subtype specificity of the risk loci in 8292 new MA and 6707 new MO cases in addition to the 6332 MA and 8348 MO cases used previously.”

Of the 123 genomic risk loci found, 86 were previously unknown, and 4 were the first to reach genome-wide significance in MA (P < 5 × 10−8).

Using linkage disequilibrium score (LDSC), authors estimated single nucleotide polymorphisms (SNP) heritability was “11.2% (95% CI, 10.8–11.6%) on a liability scale when assuming a population prevalence of 16%.”

In addition, the study identified 2 new risk loci that contain genes whose protein products are similar to targets of migraine therapies (CALCA/CALCB and HTR1F). Specifically, CALCA/CALCB encodes calcitonin gene-related peptide (CGRP), a molecule blocked by CGRP inhibitors such as erenumab. Meanwhile, the HTR1F gene “encodes serotonin 5-HT1F receptor, which is the target of another recent migraine drug class called ditans,” authors said.

Variants rs12598836 in the HMOX2 locus, rs10405121 in the CACNA1A locus and rs11031122 in the MPPED2 locus were found to be MA-specific with a probability over 95%, while rs7684253 in the locus near SPINK2 and rs8087942 in the locus near FECH were MO-specific.

“Of these variants, CACNA1A is a well-known gene linked to familial hemiplegic migraine, a rare subform of MA,” authors wrote.

Furthermore, “loci (for example, LRP1 and FHL5) that are strongly associated with both subtypes provide convincing evidence for a previous hypothesis that the subtypes partly share a genetic background,” they added.

Tissue enrichment analyses indicated both vascular and central nervous tissue types play a role in migraine, along with types of the digestive system and ovary.

Although the statistical evidence for ovary involvement is weaker than that of the central nervous or vascular system, researchers noted its potential significance as females are more likely to experience migraine. Previous research has also indicated sex hormones may play a role in its pathogenesis.

The discovery of 2 GWAS associations near genes already targeted in migraine treatment “suggests that there could be other potential drug targets among the new loci, and provide a clear rationale for future GWAS efforts to increase the number of loci by increasing sample sizes further,” authors wrote. “Using genetic evidence when selecting new drug targets is estimated to double the success rate in clinical development,” they added.

Despite the links identified, more methodological work is needed to prioritize genes using computational approaches researchers stressed, while the fact migraine diagnoses are largely self-reported marks a limitation to the current analysis.

Studies with larger samples are also warranted to better elucidate similarities and differences in genetic architecture of MA and MO.

“We expect that these and future GWAS data will reveal more of the heterogeneous biology of migraine and potentially point to new therapies against migraine—a leading burden for population health throughout the world,” researchers concluded.


Hautakangas H, Winsvold BS, Ruotsalainen, et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat Genet. Published online February 3, 2022. doi:10.1038/s41588-021-00990-0

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