Abstract for presentation at 11th International Congress of Human Genetics

Fine Mapping of a putative susceptibility locus on Chromosome 10 for Multiple Sclerosis in an Anglo-Celtic population

  • Melanie Bahlo, Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Jim Stankovich, Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Justin Rubio, Howard Florey Institute, Australia
  • Prof Trevor Kilpatrick, Howard Florey Institute, University of Melbourne, Royal Melbourne Hospital,, Australia
  • Dr Helmut Butzkueven, Howard Florey Institute, Australia
  • Prof Graeme Stewart, Walter and Eliza Hall Institute of Medical Research, UC Berkeley, Australia
  • Prof Terence Speed, Walter and Eliza Hall Institute of Medical Research, UC Berkeley, Australia
  • Prof Simon Foote, Menzies Research Institute, Hobart, Australia

    • We conducted a genome wide haplotype association study using 170 Multiple Sclerosis (MS) patients and 105 controls of Tasmanian origin. Using haplotype association mapping methods we identified a suggestive association signal (p-value =0.005) on chromosome 10. Subsequent fine mapping with 9 additional microsatellite markers supported the association signal (OR =1.63 for the susceptibility haplotype) which spanned 7.5 cM. This putative MS susceptibility locus interacts with the HLA region, a known MS association, with individuals that have the HLA DR15 haplotype mainly contributing to the association signal. SNP fine mapping was carried out with 222 SNP markers using a subset of the genome wide scan families plus additional small sibships from Victoria with the same selection criteria as the genome wide scan data giving a total of 359 sibships. Two regions of significant association were identified using TDT analysis, however one was distal and the other proximal of the original peak signal. The distal signal was the more promising and a further 78 SNPs were chosen to extend the distal coverage. Subsequent TDT and FBAT analysis identified a signal (nominal p-value<0.05) at 35 SNPs, covering a 200kb region. Four of these SNPs remain significant after multiple testing adjustments. This region spans exons 1, 2 and intron 1 of gene X and shows extended linkage disequilibrium in our sample.
    The Tasmanian population is of Anglo-Celtic origin. The chromosome 10 signal appears to be an Anglo-Celtic phenomenon with HLA interaction with the DR15 haplotype which is elevated in the Anglo-Celtic population in comparison to other populations. We are currently seeking to replicate this result and conducting further fine mapping of the promoter of gene X.

    Conference Organiser - ICMS Pty Ltd