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Multi-Ethnic Migraine GWAS Uncovers Risk Loci Specific to Sex, Ancestry

NEW YORK – A new genome-wide association study meta-analysis has uncovered dozens of loci with previously unappreciated ties to migraine headache risk.

The newly detected risk loci, together with loci linked to migraine in the past, "provide potential causal variants, candidate genes, and relevant pathways underlying migraine susceptibility," first and corresponding author Hélène Choquet, a researcher with Kaiser Permanente Northern California, and her colleagues wrote.

As they reported in Communications Biology on Thursday, the researchers considered array-based genotyping profiles for more than 550,000 participants of European, East Asian, African American, or Hispanic/Latino ancestry from the Genetic Epidemiology Research in Adult Health and Aging study or the UK Biobank project for their initial GWAS meta-analysis.

In addition to this multi-ethnic analysis, the team brought in summary statistics from a previous GWAS spanning nearly 375,800 migraine cases or controls from the International Headache Genetics Consortium for a meta-analysis focused on individuals with European ancestry.

Together, these data highlighted 79 loci with significant ties to migraine, the investigators reported, including 45 loci not linked to the neurological condition in the past. They also narrowed in on three loci in or around the CPS1, PBRM1, and SLC25A21 genes that appeared to be associated with migraine susceptibility specifically in women, who tend to suffer from the condition at higher rates than men.

In a meta-analysis that included participants from multiple ancestral backgrounds, meanwhile, the team flagged 22 migraine-related loci — a set that encompassed 10 loci not linked to the headaches in the past. In the participants of European descent, an ancestry-specific migraine GWAS led to 35 new and 38 known risk loci, while conditional and joint analyses of data from the European participants led to two more migraine-linked loci.

On the other hand, the investigators did not detect additional risk loci in meta-analyses focused on East Asians or Africans, perhaps owing to smaller case and control numbers in these ancestry groups, though there were hints that biological sex can impact the repertoire of genetic variants contributing to migraine risk.

A gene-based analysis pointed to dozens of genes with significant ties to migraine risk, the investigators noted, along with 15 genes that fell in or near migraine-related loci from the European ancestry analysis. They also saw hints that some of the same variants influencing migraine risk may affect the expression of genes in the sigmoid colon, esophagus, or cardiovascular system, or showed some overlap with variants implicated in other conditions ranging from pain medication response to anxiety, depression, or insomnia.

"[O]ur results identified additional loci that contribute to migraine susceptibility and represent potential candidates for the development of new therapeutic targets for this common neurological cause of disability," the authors concluded. "Although these findings will help to better understand the etiology of migraine susceptibility, additional genetic studies are needed to validate these associations in more large cohorts."

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