Haplotype Analysis of X Linked Migraine Pedigrees Refines the Migraine Susceptibility Locus to Xq24. L.R. Griffiths1, D.R. Nyholt1, R.A. Lea1, R.P. Curtain1, P.J. Brimage2. 1) Genomics Res Ctr, School Health Science, Griffith Univ, Southport QLD, Australia 4217; 2) Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
Recent studies in our laboratory have provided evidence for a X linked genetic component in familial typical migraine [1]. Using two large multigenerational pedigrees, designated MF7 and MF14, we were able to demonstrate significant excess allele sharing with a number of Xq microsatellite markers; MF7 giving a maximum NPL score of 2.57 at DXS1001, (P = 0.031) and MF14 giving a NPLmax of 2.74 at DXS1123 (P = 0.012). However, although combined analysis of the two pedigrees indicated excess allele sharing more towards the MF14 peak, the fact that the different peak regions of MF7 and MF14 were approximately 46cM apart, clearly indicated the need for finer gene mapping in these pedigrees. Therefore, to further localise and increase the information content across the implicated regions on chromosome Xq, the present study utilised additional microsatellite markers combined with haplotype analysis. Multipoint linkage analysis of genotype results was performed using the Sall scoring function in the GENEHUNTER-PLUS package, whilst reconstruction of the most likely haplotypes and determination of crossover events were calculated using the exact-likelihood method implemented in GENEHUNTER. Results from the study indicated significant evidence for X-linkage, with a peak LOD score of 2.388 (P = 0.0005) equidistant between DXS1001 and HPRT. Haplotype analysis was able to reduce this region further, indicating that the most likely localisation for the migraine susceptibility gene is the within a 5Mb region on the X chromosome. Hence we have provided further evidence for the location of a X chromosomal migraine gene and have been able to more firmly localise this locus to Xq24.