Genetic mapping and association analysis in multiple sclerosis

Abstract: Multiple sclerosis (MS) is a chronic neurological disease. Epidemiological studies have shown evidence for both environmental and genetic involvement of the disease. The contribution of genes versus environment is complex, in that there is not one major gene causing the disease, but more likely several genes each contributing to a modest extent and most likely interacting in a complex manner. Studies on genetic susceptibility in complex traits mainly rely on either of two principally different methods; Candidate gene analysis, where potential candidate genes are chosen based on the existing knowledge of pathogenic mechanisms; or genome-wide screens, where an unbiased selection of markers covering the genome with a density of about 10-15 cM between the markers (300-400 markers to cover the genome) is used for linkage analysis without previous assumption about the underlying pathology of the disease. The high prevalence of multiple sclerosis (-130/100,000) in Scandinavia and the striking correlation between its global geographical distribution and the migration pattern of Northern Europeans have suggested that important susceptibility alleles may initially have arisen in Scandinavia. In order to facilitate analysis of the disease in this potentially founding population, a collaborative group was formed in 1994 (the Nordic MS Genetics Group) involving eight Nordic research centers with the aim to identify familial multiple sclerosis in Scandinavia in order to establish a resource for genetic analysis. Study I was a genome-wide screen for linkage in 136 Nordic sib-pairs with multiple sclerosis that had been identified through the Nordic collaboration. Although the results showed no regions of genomewide significance, 17 regions were identified where the led score exceeded 0.7 (the 5% nominal significance level). These regions include 1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. In a genome wide screen of this density, only ten such regions would be expected by chance alone. The fact that our results exceed expectation suggests that some of these peaks are likely to be genuine. One of the regions showing potential linkage in the Nordic screen was located on the short arm of chromosome 10. This chromosomal area has also shown partially overlapping peaks in several previous genome-wide screens including the screens from Italy, Sardinia, United Kingdom, as well as the latest meta-analysis of all genome-wide screens performed in multiple sclerosis. In study II we explored this region by genotyping 13 microsatellite markers in 449 sib-pairs with multiple sclerosis from the Nordic populations as well as United Kingdom, Sardinia and Italy. This study showed increased support for suggestive linkage on 10p15 (MLS 2.5). Study III is an association analysis of the gene coding for the alpha-receptor of IL-15 (IL-15RA). This gene is located in the area of the peak on 10p15 that was found to give suggestive linkage in Study 11. In this study, six singlenucleotide polymorphisms (SNPs) in the gene were genotyped in 553 patients with multiple sclerosis and 530 healthy controls. The study did not show any association for IL-15RA to multiple sclerosis, neither in single-point analysis nor haplotype analysis, making it less likely that this is the gene responsible for the peak in this region in the linkage analysis. In parallel with the published genome-wide screens for linkage in multiple sclerosis, a genome-wide linkage screen had been performed in a cohort of Icelandic families with multiple sclerosis. This screen showed a haplotype on chromosome 10p12, potentially associated with multiple sclerosis in these Icelandic families. As this region overlaps with our previous findings, we in study IV decided to investigate this chromosomal area in a cohort of Swedish patients with MS and controls. Although we could not show any definite significantly associated haplotypes, we detected a marginal significant core haplotype in the Swedish MS cohort overlapping a haplotype shared in four affected sibs in one Icelandic family, giving some support for continuing the genetic research in the region as one of the candidate regions for susceptibility genes for MS.