An X Chromosome Association Scan of the Norfolk Island Genetic Isolate Provides Evidence for a Novel Migraine Susceptibility Locus at Xq12

作者：Maher Bridget H^*; Lea Rod A; Benton Miles; Cox Hannah C; Bellis Claire; Carless Melanie; Dyer Thomas D; Curran Joanne; Charlesworth Jac C; Buring Julie E; Kurth Tobias; Chasman Daniel I; Ridker Paul M; Schuerks Markus; Blangero John; Griffiths Lyn R

来源：PLos One, 2012, 7(5): e37903.

DOI：10.1371/journal.pone.0037903

Migraine 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 x 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 x 10(-4)), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65 x 10(-4)). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women%26apos;s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P%26lt;0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63 x 10(-5)) is located within the 5%26apos;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.

• 出版日期2012-5-29