A genome scan in a single pedigree with a high prevalence of multiple sclerosis.
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.
Dyment
D A
DA
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Cader
M Z
MZ
Herrera
B M
BM
Ramagopalan
S V
SV
Orton
S M
SM
Chao
M
M
Willer
C J
CJ
Sadovnick
A D
AD
Risch
N
N
Ebers
G C
GC
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
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen