THE GENETICS OF MULTIPLE-SCLEROSIS - PRINCIPLES, BACKGROUND AND UPDATED RESULTS OF THE UNITED-KINGDOM SYSTEMATIC GENOME SCREEN

Genetic susceptibility to multiple sclerosis is implicated on the basi s of classical family studies and phenotype analyses. The only reprodu cible legacy from the candidate gene approach has been the discovery o f population associations with alleles of the major histocompatibility complex; Systematic genome scanning has since been applied using a pa nel of anonymous markers to identify areas of linkage in co-affected s iblings. Here, we describe the principles of genome screening and upda te the UK survey of multiple sclerosis. This identified 20 regions of potential interest, but in none was there unequivocal linkage. In theo ry, attempting to replicate these findings in a second set of sibling pair families is the most appropriate way to distinguish true from fal se positives, but unfortunately the number of families required to do this reliably is prohibitively large. We used three approaches to incr ease 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-b y-chromosome account is given to direct future searches. Although an a dditional marker placed distal to the 'hit' on chromosome 14q increase d linkage in this area, and typing extra sibling pairs increased linka ge on chromosomes 6p and 17q, evidence for linkage was more commonly r educed and no additional regions of interest were found. A further ref inement of the genome screen was undertaken by conditioning for the pr esence of HLA-DR15. This produced a surprising degree of segregation a mong the regions of interest, which divided into two distinct groups d epending on DR15 sharing: the DR15-sharing cohort comprised loci on ch romosomal areas Ip, 17q and X; and the DR15-non-sharing cohort was mad e up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlig hts the genetic complexity of multiple sclerosis. What can now be infe rred 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 ver y small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on indep endent or epistatic effects of several genes each with small individua l effects, rather than a very few genes of major biological importance .