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

Abstract

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.

Exclusion of the 750‐kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy in HPCX1‐linked families

“…It is worth noting that in addition to HPCX1, other disease-associated loci were mapped to Xq27-q28, including the TGCT locus linked to hereditary testicular cancer and the susceptibility loci for dyslexia, autism and migraine (Lutke et al 2004; de Kovel et al 2004; Slavotinek et al 2005; Vincent et al 2005; Maher et al 2012). Therefore, the study of newly identified coding regions in a series of these disorders would be warranted.…”

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

“…The female preponderance of migraine suggests the disease is partly influenced by X-linked genomic factors. 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.…”

“…We analysed the X chromosomal data from a recent genome-wide association study [7] using a two-step method. We decided to separate the X chromosome from the autosomal analysis due to the specific X-linked hypothesis being tested and our previous findings regarding X chromosome loci and migraine [8] , [9] , [10] . Step one involved a preliminary scan of the data using a logistic regression association study approach controlling for age and gender.…”

“…This increased prevalence in women may be partially attributed to genes located on the X chromosome. Previous work from our laboratory has implicated X chromosome loci at Xq24, Xq27 and Xq28 in Australian migraine pedigrees [8] , [9] , [10] .…”

Migraine Genetics: PartII

“…The possibility of migraine as an X‐linked disorder is suggested by the female preponderance of and evidence that a high proportion of affected males have a greater number of affected first‐degree relatives . In a linkage analysis of 6 migraine pedigrees and a case–control cohort study that evaluated 11 candidate genes, 2 distinct susceptibility variants were identified at Xq27 (marked by DXS8043—DXS297) and Xq28 (DXS8061—XqTer) . Because these susceptibility regions were also associated in the case–control population, the possibility was raised that these loci are not pedigree‐specific and may be contributing to migraine in the general population.…”