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A genome-scan in a single pedigree with a high prevalence of multiple sclerosis
  1. D A Dyment (ddyment{at}
  1. University of Oxford, United Kingdom
    1. M Z Cader (zameel{at}
    1. University of Oxford, United Kingdom
      1. M B Herrera (sorton{at}
      1. University of Oxford, United Kingdom
        1. S V Ramagopalan (sreeram{at}
        1. University of Oxford, United Kingdom
          1. S M Orton
          1. University of Oxford, United Kingdom
            1. M Chao (michael.chao{at}
            1. University of Oxford, United Kingdom
              1. C J Willer (cwiller{at}
              1. University of Oxford, United Kingdom
                1. A D Sadovnick (sadovnik{at}
                1. University of British Columbia, United Kingdom
                  1. N Risch (rischn{at}
                  1. UCSF, United States
                    1. G C Ebers (george.ebers{at}
                    1. University of Oxford, United Kingdom


                      Background: Multiple sclerosis (MS) is a disease widely believed to be autoimmune in nature. Genetic-epidemiological studies implicate susceptibility genes in pathogenesis, although non-MHC susceptibility linkages have been difficult to confirm. Insight into pathways intrinsic to other complex diseases has come from the genetic analysis of large, autosomal dominant kindreds. Here we present a genetic study of a large and unique kindred in which MS appears to follow an autosomal dominant pattern of inheritance with consistent penetrance in 4 generations.

                      Methods: Eighty-two individuals of this 370 member family were genotyped with 681 microsatellite markers spanning the genome with an average spacing of 5.3 cM.

                      Results: Parametric linkage analysis was performed and no significant LOD score (LOD>3.3) was observed. For a rare dominant disease model with reduced penetrance, 99.6% of the genome was excluded at a lod score <-1 and 96% at a lod score <-2. The HLA-DRB1 candidate gene was also genotyped by allele-specific methods. In each instance where at least one parent was positive for HLA-DRB1*15, one or more HLA-DRB1*15 alleles were transmitted to the affected offspring (11/11). HLA-DRB1*15 was transmitted equally from both the familial and the married-in parents and therefore this locus does not appear to be the autosomal dominant acting gene in this family but an important modifier of risk.

                      Conclusions: These results further stress the importance of the HLA-DRB1*15 bearing haplotype in determining MS susceptibility. Furthermore this study highlights the complexity of MS genetics; even in the presence of a single family seemingly segregating MS as an autosomal dominant trait.

                      • HLA
                      • genome
                      • linkage
                      • multiple sclerosis

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