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Three Dozen Migraine Susceptibility Loci Uncovered in Large Meta-Analysis

NEW YORK (GenomeWeb) – Researchers from the International Headache Genetics Consortium have linked more than three dozen loci to migraine susceptibility.

As the consortium reported today in Nature Genetics, it conducted a meta-analysis of 22 genome-wide association studies and uncovered 44 independent SNPs linked to migraine risk that mapped to 38 different loci. These included 28 novel loci and were enriched in genes that are expressed in vascular and smooth muscle tissues.

"[T]he 38 genomic loci identified in this study support the notion that factors in vascular and smooth muscle tissues contribute to migraine pathophysiology and that the two major subtypes of migraine — migraine with aura and migraine without aura — have a partially shared underlying genetic susceptibility profile," Massachusetts General Hospital and Harvard Medical School's Aarno Palotie and his colleagues wrote in their paper.

Palotie and his colleagues bundled together 22 GWAS, which included nearly 60,000 people suffering from migraine, both with and without aura, and 316,000 controls, all of European ancestry. They imputed missing genotypes using a 1000 Genomes Project reference panel.

In their primary analysis, which examined more than 8 million variants, the researchers identified 44 independent genome-wide significant SNP associations. After merging nearby associated loci together, they linked 38 genomic loci to migraine, 28 of which had never before been linked to the condition. These loci, the researchers noted, replicated 10 of the 13 loci that had been previously linked with migraine in previous work.

The investigators also searched for associations with migraine subtypes. For migraine without aura — the most common form of the condition — they identified seven significant loci, all of which had been uncovered in the primary analysis. However, they were unable to associate any loci specifically with migraine with aura, likely because of its smaller sample size. Still, their heterogeneity analysis suggested that most of the identified loci were involved in both migraine types.

Some 84 percent of these 38 loci overlapped with transcripts from protein-coding genes, the researchers reported, and 45 percent of these regions include just one gene. Of these 38 loci, only two implicated ion channel genes, minimizing the hypothesis that migraine might be a channelopathy.

Instead, a number of these implicated genes have previously been linked to vascular disease, like PHACTR1, TGFBR2, and HEY2, while others have roles in smooth muscle contractility and the regulation of vascular tone, like MRVI1, GJA1, and NRP1.

By drawing on data from the Genotype-Tissue Expression Consortium project, the researchers noted that some disease-linked genes were more highly expressed in certain tissue groups. For instance, GPR149, CFDP1, and DOCK4 were more highly expressed in the brain, while PRDM16, MEF2D, and FHL5 were more highly expressed in vascular tissues.

Palotie and his colleagues also searched for tissues that are enriched for the expression of these 38-migraine associated genes. Based on this analysis, they found that the most strongly associated tissues were part of the cardiovascular system, though tissues in the digestive system also showed enrichment. They replicated this finding using the DEPICT tool and an independent microarray-based dataset.

Further lines of evidence, including a Gene Ontology over-representation and a second DEPICT-based analysis, also underscored the involvement of vascular tissue. Finding such a link to vascular tissue is consistent with migraine comorbidities and previously reported shared polygenic risk among migraine, stroke, and cardiovascular disease, the researchers noted.

"These results suggest that vascular dysfunction and possibly also smooth muscle dysfunction are likely to have roles in migraine pathogenesis," Palotie and his colleagues wrote. However, they also added that neurogenic mechanisms are likely involved in migraine as well.