An x chromosome association scan of the norfolk island genetic isolate provides evidence for a novel migraine susceptibility locus at xq12

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

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere37903
JournalPloS one
Volume7
Issue number5
DOIs
StatePublished - May 29 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Maher, B. H., Lea, R. A., Benton, M., Cox, H. C., Bellis, C., Carless, M., Dyer, T. D., Curran, J., Charlesworth, J. C., Buring, J. E., Kurth, T., Chasman, D. I., Ridker, P. M., Schürks, M., Blangero, J., & Griffiths, L. R. (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]. https://doi.org/10.1371/journal.pone.0037903