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

Xq12 Haplotype Analysis.

*<p>Block 1 consists of SNPs: rs6525037 rs6525038 rs5964480 rs5965083 rs5964486 rs5964488 rs1977106 rs670546 rs599958 rs5918974 rs5918577.</p>+<p>Block 2 consists of SNPs: rs760867 rs5919015 rs1028348 rs7054364 rs1011526.</p

Xq27 Haplotype Analysis.

*<p>Block 1 consists of SNPs: rs4827700 rs4263905 rs5920061 rs12014291 rs910618 rs6525667.</p>+<p>Block 2 consists of SNPs: rs4827703 rs5920067 rs12555969 rs1339482 rs5920070 rs1998005.</p

Norfolk Island X chromosome Scan.

<p>Norfolk Island X chromosome Scan.</p

Linkage Disequilibrium plots.

<p>a) Xq12 locus b) Xq27 locus.</p

Top 25 SNPs ranked by P-value.

<p>Top 25 SNPs ranked by P-value.</p