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Migraine GWAS Points to Subtype-Specific Loci, Potential Mechanisms


NEW YORK – An international team led by investigators at the University of Helsinki's Institute for Molecular Medicine Finland has uncovered more than 100 loci linked to migraine susceptibility, including risk variants not found in the past and loci implicated in migraine subtypes.

"These subtypes (migraine with aura and migraine without aura) have been defined by symptoms of migraine patients. Identification of subtype-specific genetic risk factors tells us that there are biological differences between these subtypes and points us to some of those differences," senior author Matti Pirinen, a molecular medicine, public health, and mathematics and statistics researcher at the University of Helsinki, said in an email. "Such information can be valuable when the final aim is to develop an effective treatment for a particular patient."

With a genome-wide association study involving 102,084 migraine-affected individuals and nearly 771,300 unaffected controls, the researchers focused in on 123 migraine-associated loci — a set that included 86 risk loci not reported in the past. Bringing in available gene expression, expression quantitative trait locus, and chromatin annotation profiles, together with findings from a phenome-wide association analysis, they highlighted migraine-associated pathways and cell types related to neurovascular or central nervous system activity and cardiovascular traits.

"It has been long debated whether migraine has a vascular or a neuronal origin, or whether it is a combination of both," the authors noted in a paper published in Nature Genetics on Thursday. "Here, we found genetic evidence for the role of both vascular and central nervous tissue types in migraine from several tissue enrichment analyses, which refined earlier analyses based on smaller sample sizes."

Meanwhile, the team's stratification analyses — based on new or published genetic data for 14,624 cases classified in the migraine with aura subtype, 15,055 migraine without aura cases, and hundreds of thousands of control individuals — pointed to five migraine subtype-specific variants, including three sites implicated in susceptibility to migraine with aura and two linked to migraine without aura. Nine more sites were associated with migraine risk across the subtypes considered.

"Our subtype analysis of migraine with aura and migraine without aura shows that these migraine subtypes have both shared risk alleles and risk alleles that seem specific to one subtype," the authors wrote, noting that "new loci include two targets of recently developed and effective migraine treatments."

Within that new risk locus collection, the authors flagged two migraine-linked loci in and around the calcitonin gene-related peptide coding gene CALCA/CALCB and the serotonin 1F receptor-coding gene HTR1F that are already being targeted by migraine drugs.

"[W]e 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," the authors concluded.