Abstract
Epidemiological studies show that susceptibility to multiple sclerosis (MS) has a strong genetic component, but apart from the HLA gene complex, additional genetic factors have proven difficult to map in the general population. Thus, localized populations, where MS patients are assumed to be more closely related, may offer a better opportunity to identify shared chromosomal regions. We have performed a genome-wide scan with 834 microsatellite markers in a data set consisting of 54 MS patients and 114 healthy family members. A group of families from a small village were possible to track back to common ancestors living in the 17th century. We used single marker- and haplotype-based transmission disequilibrium test (TDT) analysis and nonparametric linkage analysis to analyze genotyping data. Regions on chromosomes 2q23–31, 6p24–21, 6q25–27, 14q24–32, 16p13–12 and 17q12–24 were found to be in transmission disequilibrium with MS. Strong transmission disequilibrium was detected in 14q24–32, where several dimarker haplotypes were in transmission disequilibrium in affected individuals. Several regions showed modest evidence for linkage, but linkage and TDT were both clearly positive only for 17q12–24. All patients and controls were also typed for HLA class II genes; however, no evidence for a gene–gene interaction was observed.
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References
Gusella JF, Wexler NS, Conneally PM et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 1983; 306: 234–238.
Rommens JM, Iannuzzi MC, Kerem B et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059–1065.
Sadovnick AD, Armstrong H, Rice GP et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33: 281–285.
Ebers GC, Bulman DE, Sadovnick AD et al. A population-based study of multiple sclerosis in twins. N Engl J Med 1986; 315: 1638–1642.
Hillert J . Human leukocyte antigen studies in multiple sclerosis. Ann Neurol 1994; 36: (Suppl): S15–S17.
Olerup O, Hillert J . HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens 1991; 38: 1–15.
Heutink P, Oostra BA . Gene finding in genetically isolated populations. Hum Mol Genet 2002; 11: 2507–2515.
Peltonen L, Palotie A, Lange K . Use of population isolates for mapping complex traits. Nat Rev Genet 2000; 1: 182–190.
He B, Giedraitis V, Ligers A et al. Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11. Eur J Hum Genet 2002; 10: 271–275.
Landtblom AM, Boiko A, Soderfeldt B . Distribution of multiple sclerosis in Sweden based on mortality and disability compensation statistics. Neuroepidemiology 2002; 21: 167–179.
Kuokkanen S, Gschwend M, Rioux JD et al. Genomewide scan of multiple sclerosis in Finnish multiplex families. Am J Hum Genet 1997; 61: 1379–1387.
Sawcer S, Jones HB, Feakes R et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 1996; 13: 464–468.
The Transatlantic Multiple Sclerosis Genetics Cooperative. A meta-analysis of genomic screens in multiple sclerosis. Mult Scler 2001; 7: 3–11.
Sawcer S, Maranian M, Setakis E et al. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain 2002; 125: 1337–1347.
Saarela J, Schoenberg Fejzo M, Chen D et al. Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22–q24. Hum Mol Genet 2002; 11: 2257–2267.
Akesson E, Oturai A, Berg J et al. A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis. Genes Immun 2002; 3: 279–285.
Kantarci OH, Hebrink DD, Achenbach SJ et al. CTLA4 is associated with susceptibility to multiple sclerosis. J Neuroimmunol 2003; 134: 133–141.
Maurer M, Ponath A, Kruse N, Rieckmann P . CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. J Neuroimmunol 2002; 131: 213–215.
Ligers A, Xu C, Saarinen S, Hillert J, Olerup O . The CTLA-4 gene is associated with multiple sclerosis. J Neuroimmunol 1999; 97: 182–190.
Kong A, Gudbjartsson DF, Sainz J et al. A high-resolution recombination map of the human genome. Nat Genet 2002; 31: 241–247.
Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58: 1347–1363.
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Giedraitis, V., Modin, H., Callander, M. et al. Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q. Genes Immun 4, 559–563 (2003). https://doi.org/10.1038/sj.gene.6364024
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DOI: https://doi.org/10.1038/sj.gene.6364024
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