A Novel Locus for Familial Migraine on Xp22

Wieser, Thomas; Pascual, Julio; Oterino, Agusto; Soso, Michael J.; Barmada, M. Michael; Gardner, Kathy

doi:10.1111/j.1526-4610.2010.01673.x

Cited by 14 publications

(9 citation statements)

References 42 publications

(80 reference statements)

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“…Besides loci on autosomes, there were also studies that focused on sex chromosomes. For instance, migraine susceptibility loci were identified on both the long arm of the X‐chromosome (ie, Xq24‐q28) 22,23 as well as the short arm of that chromosome (ie, Xp21 19 and Xp22) 24 . Although robust replication of these findings is still lacking, several other studies 17,19,20 seem to suggest that migraine susceptibility loci are present at these chromosomal locations.…”

Section: Linkage and Candidate Gene Association Studies Of Migraine: mentioning

confidence: 99%

Migraine Genes and the Relation to Gender

2011

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Migraine is an episodic brain disorder that is characterized by recurrent attacks of severe unilateral headache that are accompanied by various neurological symptoms. In addition, many patients have what is called an aura with visual and sensory disturbances. The majority of patients are female, suggesting that female hormones play an important role in the pathophysiology of the disorder. The molecular mechanisms, however, underlying this female preponderance are not well understood. It can be expected that the field of genetics that aims at identifying genetic factors that cause migraine by lowering the threshold for attacks will unravel some of these mechanisms. The 3 best known migraine genes encode ion transporters and were identified in families with familial hemiplegic migraine (FHM), a rare subtype of migraine with aura. FHM gene mutations cause alterations in mechanisms that control and modulate the neurotransmitter balance in the brain. Transgenic mice knock-in with human pathogenic mutations that were shown to exhibit some migraine-relevant features were very helpful in dissecting molecular mechanisms of migraine and pointed to a central role for cortical glutamate. In addition, transgenic mice that overexpress human RAMP1 exist and exhibit an increased sensitivity to calcitonin gene-related peptide. Findings from genetic and animal experiments on gender differences in migraine are discussed. Recently, a role for glutamate also came forward from a genome-wide association study in common migraine. By deciphering genetic and pathogenic migraine pathways, it can be expected that in the near future we will better understand mechanisms behind the female preponderance in migraine.

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Section: Linkage and Candidate Gene Association Studies Of Migraine: mentioning

confidence: 99%

Migraine Genes and the Relation to Gender

2011

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“…A previously published study using Australian Twins also identified association at two SNPs-rs6525667 and rs910618 (both at P00.009) that localise to the Xq27 region identified here. Furthermore, a recent study investigating the X chromosome in migraine identified the Xp22 locus, however, the authors suggest that their data may also provide additional support for association at Xq24-Xq28 [19].…”

Section: Discussionmentioning

confidence: 80%

Confirmation that Xq27 and Xq28 are susceptibility loci for migraine in independent pedigrees and a case-control cohort

et al. 2012

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Investigations into migraine genetics have suggested that susceptibility loci exist on the X chromosome. These reports are supported by evidence that demonstrates male probands as having a higher proportion of affected first-degree relatives as well as the female preponderance of 3:1 that the disorder displays. We have previously implicated the Xq24-28 locus in migraine using two independent multigenerational Australian pedigrees that demonstrated excess allele sharing at the Xq24, Xq27 and Xq28 loci. Here, we expand this work to investigate a further six independent migraine pedigrees using 11 microsatellite markers spanning the Xq27–28 region. Furthermore, 11 candidate genes are investigated in an Australian case-control cohort consisting of 500 cases and 500 controls. Microsatellite analysis showed evidence of excess allele sharing to the Xq27 marker DXS8043 (LOD* 1.38 P00.005) in MF879 whilst a second independent pedigree showed excess allele sharing to DXS8061 at Xq28 (LOD* 1.5 P00.004). Furthermore, analysis of these key markers in a case control cohort showed significant association to migraine in females at the DXS8043 marker (T1 P00.009) and association with MO at DXS8061 (T1 P00.05). Further analysis of 11 key genes across these regions showed significant association of a three-marker risk haplotype in the NSDHL gene at Xq28 (P00.0082). The results of this study add further support to the presence of migraine susceptibility loci on chromosome Xq27 and Xq28 as well as point to potential candidate genes in the regions that warrant further investigation.

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“…To date migraine susceptibility loci have been convincingly mapped to Xq24–28 and suggestively mapped to Xp22, mainly via pedigree linkage studies [8], [9], [10], [11]. For complex disease such as migraine the interplay between multiple genetic factors can make it difficult to distinguish the role each factor plays in the pathophysiology of disease.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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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.

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A Novel Locus for Familial Migraine on Xp22

Cited by 14 publications

References 42 publications

Migraine Genes and the Relation to Gender

Migraine Genes and the Relation to Gender

Confirmation that Xq27 and Xq28 are susceptibility loci for migraine in independent pedigrees and a case-control cohort

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

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