A genome scan in a single pedigree with a high prevalence of multiple sclerosis
- D A Dyment1,
- M Z Cader1,
- B M Herrera1,
- S V Ramagopalan1,
- S M Orton1,
- M Chao1,
- C J Willer1,
- A D Sadovnick2,
- N Risch3,
- G C Ebers1
- 1The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- 2Department of Medical Genetics and Faculty of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada
- 3Department of Genetics, Institute for Human Genetics, UCSF, CA, USA
- Prof. George Ebers, Department of Clinical Neurology, John Radcliffe Hospital, West Wing, University of Oxford, Oxford OX3 9DU, UK; george.ebers{at}clneuro.oxford.ac.uk
- Received 13 April 2007
- Revised 23 May 2007
- Accepted 23 May 2007
- Published Online First 5 June 2007
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.
Footnotes
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Competing interests: None declared.
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Note added in proof: During the submission process, two susceptibility genes were identified by large-scale association studies (The International Multiple Sclerosis Consortium. N Engl J Med 2007;357:851–62; Gregory et al. Nat Genet 2007;39:1083–91; Lundmark et al. Nat Genet 2007;39:1008–13). The genes, IL7RA and IL2RA, are located on 5p13 and 10p15, respectively. The genomic regions were excluded (LOD L2) in this pedigree with both rare and common disease allele models.
