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

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.

Selectivity in Genetic Association with Sub-classified Migraine in Women

“…Recent reports have described a greater number of highly significant common genetic variants for MO than MA in genome-wide analyses, as well as only partial overlap between the sets of identified genes [11] – [13] . One possible explanation of the apparent discrepancy between heritability estimates and yield of genome-wide significant associations may be different genetic contributions to MA v. MO with, for example, the former possibly characterized by genetic variants that are rarer or more population specific, or more heterogeneous compared with the latter [14] , [15] . Similarly, it is possible that a dichotomy in the genetic architecture may underlie the additional features that often accompany migraine headache, i.e.…”

Population-based approaches to genetics of migraine

“…Another unusual cohort of migraineurs consists of the inbred Norfolk Island descendants of the Bounty, whose complex pedigree has an exceedingly high prevalence of migraine of almost 26%. A candidate migraine variant on the X-chromosome from this pedigree was supported in a population-based sample of common migraine (85,86). As in the history of human genetics, these examples illustrate the potential for unusual ascertainment scenarios focused around the clinic for discovery of migraine associations that may not have been found by a population-based analysis but nevertheless may still provide insights into migraine pathophysiology.…”

Exploring the Hereditary Nature of Migraine

“…Numerous migraine studies demonstrate a preponderance of migraine in females. 12,16,27,[80][81][82] A population study by Stewart et al 83 showed that in 1992, 18% of women suffered from migraine compared to 6% of men, setting the incidence rate at 3:1. This unequal distribution of gender in migraine sufferers is common to both MO and MA, 81,[83][84][85][86][87] suggesting either a hormonal link to migraine or possibly an X-chromosomal link if there is a dominant inheritance pattern.…”