Genetic susceptibility to MS: a second stage analysis in Canadian MS families

Abstract

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

Multiple sclerosis genetics

“…Adding more microsatellite markers to the initial genome screens also failed to produce new MS-associated genes Dyment et al, 2004b;Kenealy et al, 2004). Pooling data for meta-analysis was similarly of no help in identifying loci other than the MHC (Dyment et al, 2001;GAMES, Transatlantic Multiple Sclerosis Genetics Cooperative, 2003). Consequently, it became clear that the identification of the other effects of genetic variations impacting MS susceptibility would require not only better markers but also a substantially increased number of families to reach necessary statistical power.…”

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations

“…1 The prevalence pattern may be explained, at least in part, by migrations of northern European groups and their descendants which strengthens the hypothesis of genetic factors contributing to MS. 2 Epidemiological studies performed in twins and siblings clearly indicate the impact of genetic factors. 3,4 In addition, the geographical distribution of MS and studies of migrants also suggest a considerable contribution of environmental factors that may not be evenly distributed over the world.…”

Mapping candidate non-MHC susceptibility regions to multiple sclerosis

“…A combined genomic map of MS was constructed using 170 microsatellite markers or regions previously reported in whole genome linkage screens 2-14 and their follow-up studies, [20][21][22][23][24][25] and 263 'top-ranked' markers reported in the case-control association studies of the GAMES project. 15 These markers or regions were selected based on the statistics reported in the original studies, including both significant and suggested occurrences.…”