Brain, Vol 121, Issue 10 1869-1887, Copyright © 1998 by Oxford University Press
J Chataway, R Feakes, F Coraddu, J Gray, J Deans, M Fraser, N Robertson, S Broadley, H Jones, D Clayton, P Goodfellow, S Sawcer and A Compston
Genetic susceptibility to multiple sclerosis is implicated on the basis of
classical family studies and phenotype analyses. The only reproducible
legacy from the candidate gene approach has been the discovery of
population associations with alleles of the major histocompatibility
complex. Systematic genome scanning has since been applied using a panel of
anonymous markers to identify areas of linkage in co-affected siblings.
Here, we describe the principles of genome screening and update the UK
survey of multiple sclerosis. This identified 20 regions of potential
interest, but in none was there unequivocal linkage. In theory, attempting
to replicate these findings in a second set of sibling pair families is the
most appropriate way to distinguish true from false positives, but
unfortunately the number of families required to do this reliably is
prohibitively large. We used three approaches to increase the definition
achieved by the screen: (i) the number of sibling pairs typed in an
identified region of potential linkage was extended; (ii) the information
extraction was increased in an identified region; and (iii) a search was
made for missed regions of potential linkage. Each of these approaches has
considerable limitations. A chromosome-by-chromosome account is given to
direct future searches. Although an additional marker placed distal to the
'hit' on chromosome 14q increased linkage in this area, and typing extra
sibling pairs increased linkage on chromosomes 6p and 17q, evidence for
linkage was more commonly reduced and no additional regions of interest
were found. A further refinement of the genome screen was undertaken by
conditioning for the presence of HLA-DR15. This produced a surprising
degree of segregation among the regions of interest, which divided into two
distinct groups depending on DR15 sharing: the DR15-sharing cohort
comprised loci on chromosomal areas 1p, 17q and X; and the DR15-non-sharing
cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result
further highlights the genetic complexity of multiple sclerosis. What can
now be inferred is that a gene of major effect is excluded from 95% of the
genome and one with a moderate role from 65%, whereas genes which make a
very small biological contribution cannot be discounted from any region.
The available results suggest that multiple sclerosis depends on
independent or epistatic effects of several genes each with small
individual effects, rather than a very few genes of major biological
importance.
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The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen
University of Cambridge Neurology Unit, Addenbrooke's Hospital, UK.
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