Migraine is a common and debilitating neurovascular disorder. Numerous studies have demonstrated a preponderance of women affected with migraine and previous linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-q28. The present study continues this line of investigation by performing a complete X chromosome scan of a large pedigree from the genetic isolate of Norfolk Island.
A novel pedigree-based association approach incorporating logistic regression was employed to analyse X chromosome-wide SNP data (15,154 SNPs). Data was ascertained for n=288 related individuals comprising a large core-pedigree of the Norfolk population. This pedigree is comprised of 76 individuals affected with IHS-diagnosed migraine. All SNPs were ranked based on P-values adjusted for the effects of relatedness, gender and age.
SNP prioritization showed that the top 25 SNPs contained 11 SNPs localized to the previously identified susceptibility locus on Xq27, adding further support to the involvement of this genomic region in migraine. Furthermore, 10 of the top 25 SNPs also mapped to a new locus at Xq12. Haplotype analysis highlighted 2 major haplotype blocks at Xq12 each containing a haplotype significantly over-represented in migraineurs (P<0.0005). Follow-up analysis of the Xq12 SNPs showed evidence of association in the large Women’s Genome Health Study cohort at rs1028348, located within the 5’UTR of the HEPH gene.
Overall, this study provides compelling evidence for involvement of the Xq27 region and a novel susceptibility locus on Xq12. The strongest associated SNP (rs102834) yielded a combined P-value of 1.1x10-6 and is located in the HEPH gene, a neuronally expressed gene involved in iron homeostasis, and this may represent a novel pathway for involvement in migraine pathogenesis. Investigations are now underway examining these Xq12 haplotypes in unrelated case-control populations to determine whether this locus is unique to Norfolk or influences migraine susceptibility more generally.