title: A genome scan in a single pedigree with a high prevalence of multiple sclerosis.
abstract: BACKGROUND
  Multiple sclerosis (MS) is a disease that is widely believed to be autoimmune in nature. Genetic-epidemiological studies implicate susceptibility genes in the pathogenesis of MS, although non-MHC susceptibility linkages have been difficult to confirm. Insight into pathways that are 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 four 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 an 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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Dyment
authors.forename: M Z
authors.initials: MZ
authors.lastname: Cader
authors.forename: B M
authors.initials: BM
authors.lastname: Herrera
authors.forename: S V
authors.initials: SV
authors.lastname: Ramagopalan
authors.forename: S M
authors.initials: SM
authors.lastname: Orton
authors.forename: M
authors.initials: M
authors.lastname: Chao
authors.forename: C J
authors.initials: CJ
authors.lastname: Willer
authors.forename: A D
authors.initials: AD
authors.lastname: Sadovnick
authors.forename: N
authors.initials: N
authors.lastname: Risch
authors.forename: G C
authors.initials: GC
authors.lastname: Ebers
mesh_terms: D000483:Alleles; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009103:Multiple Sclerosis / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen