Maher, Bridget H.Lea, Rod A.Benton, MilesCox, Hannah C.Bellis, ClaireCarless, MelanieDyer, Thomas D.Curran, JoanneCharlesworth, Jac C.Schürks, MarkusBlangero, JohnGriffiths, Lyn R.Buring, JulieKurth, TobiasChasman, DanielRidker, Paul2013-03-142012Maher, Bridget H., Rod A. Lea, Miles Benton, Hannah C. Cox, Claire Bellis, Melanie Carless, Thomas D. Dyer, et al. 2012. An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12. PLoS ONE 7(5): e37903.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:10406327Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci. An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical \(\alpha\) = 1×10\(^{−5}\)) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92×10\(^{−4}\)), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65×10\(^{−4}\)). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women’s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63×10\(^{−5}\)) is located within the 5′UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.en-USBiologyComputational BiologyPopulation GeneticsGenetic PolymorphismEvolutionary BiologyGeneticsGenome-Wide Association StudiesPopulation BiologyMedicineNeurologyHeadachesMigraineJournal Article2013-03-1410.1371/journal.pone.0037903