Genome-Wide Association Studies Identify Vascular Dysfunction to Be Major Cause of Migraine Susceptibility

David Bai, PharmD

A recent study using the 2016 genome-wide association study (GWAS) identified that vascular mechanisms, but also neuronal and metal ion homeostasis, may play a role in migraine susceptibility.

Migraine is a disease that is heavily associated with both genetic and environmental factors. Although there has been considerable progress in understanding its underlying pathology, much remains to be discovered. One area of research that investigators are examining comprises the genetic variants that may be associated with migraines. In a recent study, investigators used the 2016 GWAS to identify DNA variants that may be linked to migraines.

Investigators have conducted several GWAS in patients with migraines, with or without aura. In 2016, a meta-analysis on genomic data on previous cohorts was performed to yield a larger population sample. The data consisted of 59,674 cases and identified 44 cases of single nucleotide polymorphisms.

Based on the results of the 2016 GWAS, investigators found a vast amount of enrichment in the genes associated with the vascular system as identifiable risk factors for migraine. Tissue expression enrichment analysis was also performed and identified that arterial and gastrointestinal tissues were significantly enriched for migraine-associated genes. Four of the genes significantly enriched in vascular tissues were MEF2D, YAP1, LRP1, and JAG1.

The findings of the 2016 GWAS suggest that vascular dysfunction plays a large role in migraine susceptibility, but the investigators do not rule out neurologic dysfunction as another source of origin for migraines. Of the genes that were identified, at least 5 genes had neuronal function (PRDM16, MEF2D, FHL5, ASTN2, LRP1). Metal ion homeostasis was another contributor of migraine susceptibility, as 11 genes were identified (PRDM16, TGFBR2, REST, FHL5, NRP1, MMPED2, LRP1, ZCCHC14, RNF213, JAG1, SLC24A3). Although ion channel activity and pain signaling emerged as prominent signals of familial hemiplegic migraine, they did not appear so in this study.

The use of GWAS has been paramount in identifying various genomes that present as risk factors for migraines. Larger GWAS should be conducted in the future to identify additional risk factors and help develop more personalized treatment options for patients with migraine.

Van der Maagdenberg, Nyholt DR, Anttila V. Novel hypotheses emerging from GWAS in migraine? J Headache Pain. 2019;20(1):5. doi: 10.1186/s10194-018-0956-x.

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