Faculty Bibliography

Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.

Several studies have previously provided some albeit weak evidence for linkage or association between chromosome 19q13 and multiple sclerosis (MS) susceptibility. We performed a two-stage association analysis with 19 markers spanning 7 Mb/5.5 cM of 19q13. In stage 1 analysis (135 MS families) allelic and haplotypic associations were found with markers within or close to the ApoE-ApoC subregion. These observations were taken as a hypothesis, which was tested in stage 2 in 125 families. However, none of the initial associations were replicated suggesting that they were most likely due to chance. Linkage analysis was performed in 27 Finnish multiplex families using 10 microsatellites spanning 23 Mb/24 cM of 19q13. DNA was available from 72 MS patients and 150 unaffected relatives. Parametric and non-parametric linkage analyses did not provide evidence for linkage when all families were tested. After stratifying the families according to HLA-DR15 there was weak evidence for linkage to the 19q13.1 subregion in DR15 negative families (LOD(max)=1.8). Taken together these results do not support a major role of chromosome 19q13.2-q13.3 in MS susceptibility among Finnish MS patients, whereas conclusions on the 19q13.1 subregion are less clear and this region requires further study.

We analyzed the HLA class II haplotypes in 249 Finnish nuclear families and compared the frequencies of parental haplotypes transmitted or non-transmitted to multiple sclerosis (MS) patients. The most important predisposing haplotype was DRB1*15-DQB1*0602 (P<10(-6)) as expected and a weak predisposing effect of DRB1*04-DQB1*0302 was revealed after the elimination of DRB1*15-DQB1*0602. HLA-DRB1*01-DQB1*0501 and DRB1*13-DQB1*0603 were negatively associated with MS in transmission disequilibrium test, but only the DRB1*13-DQB1*0603 association remained significant (P=0.008) after the elimination of DRB1*15-DQB1*0602 haplotypes. Based on this study HLA class II haplotypes exhibit both predisposing and protective effects in MS.

Multiple sclerosis (MS) is an oligo- or polygenic disease but no specific susceptibility genes have been identified so far. In the Finnish population we have previously found evidence for linkage between MS and the myelin basic protein gene (here called Golli-MBP gene) suggesting that either Golli-MBP or another gene in its vicinity contributes to MS suceptibility. Here we have screened the Golli-MBP gene for nucleotide variations and carried out multipoint association analyses in a Finnish case-control data-set as well as in an independent data-set composed of 151 MS families from Finland and Sweden. In both data-sets we found association between MS and alleles in the 1.27 kilobase (kb) range at a tetranucleotide repeat element (TGGA)n which is located 1 kb upstream of the MBP exon 1. Haplotype analyses suggested that the MS-associated 1.27 kb alleles can be split into predisposing and non-predisposing variants and provided evidence that the candidate DNA region contributing to MS susceptibility should be located at the Golli-MBP gene within a 20-25 kb segment that was conserved in the predisposing haplotypes. These findings suggest a role for the Golli-MBP locus in MS susceptibility, at least in a subset of patients, and serve as a basis for highly focused attempts to identify predisposing mutation(s).

Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, non-parametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions (P = .1-.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807 (Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.

The role of genetic factors in the etiology of multiple sclerosis (MS) has been clearly demonstrated but the loci determining susceptibility to this disease remain largely unidentified. A contribution from several immune system genes has been suggested based on animal models and association/linkage analyses on MS patients and families. With the exception of the findings from the HLA complex, studies on candidate immune system genes have provided controversial results. Here we have performed genetic association and linkage analyses on four chromosomal regions containing immune system genes. A possible role for each of these loci in MS has been previously suggested. In data-sets derived from the Finnish population we found no evidence for contribution of the T-cell receptor beta chain (TCR beta chromosome 7q35), immunoglobulin heavy chain (IGH chromosome 14q32), interferon-gamma (IFN-gamma chromosome 12q14-q15) or interleukin-1 receptor antagonist/interleukin-1 beta (IL-1ra/IL-1 beta chromosome 2q14-q21) loci in the genetic susceptibility to MS.

Multiple sclerosis (MS) is a chronic inflammatory disorder characterized by multifocal damage of myelin in the central nervous system (CNS). The prevalence of this putative autoimmune disease is 0.1% in individuals of northern European origin. Family, adoption and twin studies implicate genetic factors in the aetiology. MS is widely speculated to be a multifactorial disorder with a complex mode of inheritance. Despite many studies of candidate genes, only an association with HLA-DR2-DQ6 has been generally detected, and the number of susceptibility genes remains unknown. The chronic variant of experimental allergic encephalomyelitis (EAE), a T-cell mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes of CNS observed in these demyelinating disorders. Susceptibility to EAE is also influenced by the major histocompatibility complex (MHC). Human syntenic regions to murine loci predisposing to EAE were tested as candidate regions for genetic susceptibility of MS. Three chromosomal regions (1p22-q23, 5p14-p12 and Xq13.2-q22) were screened in 21 Finnish multiplex MS families most originating from a high risk region in western Finland. Several markers yielded positive lod scores on 5p14-p12, syntenic to the murine locus Eae2. Our data provide evidence for a predisposing locus for MS on 5p14-p12.