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An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12

Citation

Maher, BH and Lea, RA and Benton, M and Cox, HC and Bellis, C and Carless, M and Dyer, TD and Curran, J and Charlesworth, JC and Buring, JE and Kurth, T and Chasman, DI and Ridker, PM and Schurks, M and Blangero, J and Griffiths, LR, 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) Article e37903. ISSN 1932-6203 (2012) [Refereed Article]


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Licensed under Creative Commons Attribution 2.5 Generic (CC BY 2.5) http://creativecommons.org/licenses/by/2.5/

DOI: doi:10.1371/journal.pone.0037903

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.

Item Details

Item Type:Refereed Article
Keywords:genomics, genetics, statistical genetics, neurogenetics
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genomics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Inherited Diseases (incl. Gene Therapy)
Author:Charlesworth, JC (Dr Jac Charlesworth)
ID Code:78794
Year Published:2012
Web of Science® Times Cited:8
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-07-26
Last Modified:2013-04-16
Downloads:0

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