A full genome search in multiple sclerosis

Abstract

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

“…Although the association of HLA class II alleles with multiple sclerosis is readily demonstrated, 8,24 the effect of this locus on susceptibility is modest and therefore evidence for linkage in this region is expected to be difficult to confirm. Previous linkage screens in out-bred populations of northern European origin (American, British and Canadian) [12][13][14] showed only modest evidence for linkage to the HLA region. Our study is in keeping with these results in that it also shows only modest evidence for linkage in the HLA-region on chromosome 6p21.…”

“…11 In multiple sclerosis, six whole genome screens for linkage have now been performed. [12][13][14][15][16][17] No one has shown unequivocal linkage, but most have identified more regions of potential linkage than expected by chance and together they provide the best available summary of the likely location of the relevant genes. 18 The high prevalence of multiple sclerosis (120/100 000) in Scandinavia 19 and the striking correlation between its global geographical distribution and the migration pattern of northern Europeans 20 suggest that important susceptibility alleles may have arisen in Scandinavia and been disseminated by their descendants-the so-called 'Viking hypothesis'.…”

Multiple sclerosis genetics: leaving no stone unturned

“…[23][24][25] Follow-up screenings in confirmatory and additional data sets have been completed as well (at least one additional large linkage study of 830 sib pairs using over 4500 single-nucleotide polymorphism or 'SNP' markers is in progress). Together, these studies identified approximately 60 genomic regions potentially involved in disease susceptibility, consistent with the long-held view that MS is a polygenic disorder.…”

Immuno- and genetic therapy in autoimmune diseases

“…4,5 Environmental factors have also been demonstrated from studies on migration and apparent epidemics. From all the genetic factors addressed, susceptibility has been clearly established with only certain MHC haplotypes in particular those containing the HLA-DR2 alleles in the Caucasian population whilst in the Mediterranean population links were found with the haplotypes containing HLA-DR4 and HLA-DR3.…”