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Brain, Vol. 125, No. 6, 1337-1347, June 2002
© 2002 Guarantors of Brain

A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility

Stephen Sawcer1, Mel Maranian1, Efrosini Setakis2, Val Curwen3, Eva Akesson1, Anke Hensiek1, Francesca Coraddu1, Richard Roxburgh1, David Sawcer1, Julia Gray1, Jackie Deans1, Peter N. Goodfellow4,5, Neil Walker2, David Clayton2 and Alastair Compston1

1 University of Cambridge Neurology Unit, Addenbrooke’s Hospital, 2 MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, 3 Human Genome Mapping Project Resource Centre, Hinxton and 4 University of Cambridge Department of Genetics, Cambridge, UK 5 Present address: GlaxoSmithKline Pharmaceuticals, Gunnels Wood Road Stevenage, Hertfordshire SG1 2NY, UK

Correspondence to: Alastair Compston, University of Cambridge Neurology Unit, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK E-mail: alastair.compston{at}medschl.cam.ac.uk

Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.


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