Rare risk variants associate with epigenetic dysregulation in migraine

Migraine has a heritability of up to 65%. Genome-wide association studies (GWAS) on migraine have identified 123 risk loci, explaining only 10.6% of migraine heritability. Thus, there is a considerable genetic component not identified with GWAS. Further, the causality of the identified risk loci remains inconclusive. Rare variants contribute to the risk of migraine but GWAS are often underpowered to detect these. Whole genome sequencing is reliable for analyzing rare variants but is not frequently used in large-scale. We assessed if rare variants in the migraine risk loci associated with migraine. We used a large cohort of whole genome sequenced migraine patients (1,040 individuals from 155 families). The findings were replicated in an independent case-control cohort (2,027 migraine patients, 1,650 controls). We found rare variants (minor allele frequency<0.1%) associated with migraine in a Polycomb Response Element in the ASTN2 locus. The association was independent of the GWAS lead risk variant in the locus. The findings place rare variants as risk factors for migraine. We propose a biological mechanism by which epigenetic regulation by Polycomb Response Elements plays a crucial role in migraine etiology.