Human Molecular Genetics, 2002, Vol. 11, No. 19 2257-2267
© 2002 Oxford University Press
Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22–q24
1Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA, USA, 2Department of Molecular Medicine, National Public Health Institute, Finland, 3Department of Obstetrics and Gynecology, ColumbiaUniversity, NY, 4Department of Neurology, University of Helsinki, Neuroscience Programme, Biomedicum-Helsinki, Haartmaninkatu 8, PL700, Helsinki, Finland, 5School of Public Health, University of Tampere, Tampere, Finland, 6Department of Neurology, Tampere University Hospital, Tampere, Finland, 7Central Hospital of Seinäjoki,Seinäjoki, Finland, 8Department of Neurology and Neuroscience, Kuopio University Hospital, Kuopio, Finland, 9Department of Neurology, Oulu University Hospital, Oulu, Finland and 10Department of Medical Genetics,University of Helsinki, Finland
Received April 24, 2002; Accepted July 5, 2002
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 
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 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.
* To whom correspondence should be addressed at: Department of Human Genetics, UCLA School of Medicine, Gonda Center, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088, USA. Tel: +1 3107945631; Fax: +1 3107945446; Email: lpeltonen{at}mednet.ucla.edu
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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