Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P50.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P50.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.

Chromosome 17p12-q11 harbors susceptibility loci for systemic lupus erythematosus

“…Further support for this region as a susceptibility region for SLE and other autoimmune diseases comes from the linkage found in a meta-analysis of MS genome scans, which identified the same broad region from 17p12 to 17q11 (Transatlantic Multiple Sclerosis Genetics Cooperative 2001). In a second study of an extended pedigree of MS from northern Sweden, a shared haplotype was found on chromosome 17p11 including markers D17S921 and D17S122 but not D17S1294 on 17q11 (He et al 2002), where we find our highest LOD score. Two genome-wide association studies from the Genetic Analysis of Multiple Sclerosis in Europeans collaboration found association with MS with "hypothetical" P-values of <0.05 for two markers on 17q11, viz., D17S1293 (Goertsches et al 2003) and D17S975 .…”

“…This locus has not been identified previously in SLE but has been identified in a metaanalysis of several multiple sclerosis (MS) genome scans (Transatlantic Multiple Sclerosis Genetics Cooperative 2001). Moreover, a conserved haplotype at 17p12 has been found in a Swedish extended pedigree with multiple cases of MS (He et al 2002). We have also found a second locus (almost reaching the level of significance) that is located on chromosome 19q13 and that has been previously linked to SLE in Swedish (Lindqvist et al 2000) and European-American families (Moser et al 1998).…”

Transgenerational response to nutrition, early life circumstances and longevity

“…27 The multifactorial disease multiple sclerosis, is common in one family in Ö verkalix. 28 In an earlier paper, we considered the possibility of genetic selection of an allele for infant survival and diabetes susceptibility for example, but no evidence of selection through differential infant mortality among ancestors with different availability of food during their SGP could be found. 2 Here we show, using sensitivity analysis, that genetic relatedness does not account for the transgenerational effects observed, so enrichment of the diabetic probands with multiple descendants from one ancestor who happened, by chance, to transmit a susceptibility allele is not an explanation.…”

Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q

“…In this respect, our data are similar to those obtained from another Swedish localized-isolated population, although only one region, chromosome 14q24-32, was clearly overlapping between these populations (Giedraitis et al, to be published). 9 Thus, clusters in two parts of Sweden seemed to be both polygenic and dependent on different genetic factors, most of which so far overlap with previously suggested MS loci. In both, the HLA genes seemed to be of only minor importance, although DR15 being a more frequent finding in patients.…”

“…7,8 Indeed, in a recent study of a localized MS population from the very north of Sweden, we have managed to identify chromosomal regions, some of which overlapped with previously identified candidate linkage regions. 9 Here, we focus on a family material collected in Värmland, a county in the west part of Sweden, where a high mortality from MS has been recorded. 10 This data set includes a number of pedigrees collected in the small village of Lysvik.…”