An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12.
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 α = 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.
Genomics Research Centre, Griffith Health Institute, Griffith University, Queensland, Australia.
Bridget H
BH
Maher
Rod A
RA
Lea
Miles
M
Benton
Hannah C
HC
Cox
Claire
C
Bellis
Melanie
M
Carless
Thomas D
TD
Dyer
Joanne
J
Curran
Jac C
JC
Charlesworth
Julie E
JE
Buring
Tobias
T
Kurth
Daniel I
DI
Chasman
Paul M
PM
Ridker
Markus
M
Schürks
John
J
Blangero
Lyn R
LR
Griffiths
D001483:Base Sequence; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008542:Melanesia; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics*; D010375:Pedigree; D015203:Reproducibility of Results
D005819:Genetic Markers