All About Multiple Sclerosis

More MS news articles for April 2004

An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15069025

Hum Mol Genet. 2004 May 15;13(10):1005-1015. Epub 2004 Apr 06
Dyment DA, Sadovnick AD, Willer CJ, Armstrong H, Cader ZM, Wiltshire S, Kalman B, Risch N, Ebers GC.
The Canadian Collaborative Study Group is: Vancouver: Donald W. Paty, Stanley Hashimoto, Virginia Devonshire, John Hooge, Lorne Kastrukoff, Joel Oger, Tony Traboulsee; Calgary: Luanne Metz; Edmonton: Sharon Warren; Saskatoon: Walter Hader; Ottawa: Mark Freedman; Kingston: Donald Brunet; Hamilton: John E. Paulseth; London: George Rice, Marcelo Kremenchutzky; Toronto: Paul O'Connor, Marika Hohol, Trevor Gray; Montreal: Pierre Duquette, Yves Lapierre; Quebec City: Jean-Pierre Bouchard; Halifax: T. John Murray, Virender Bhan, Charles Maxner, St Johns: William Pryse-Phillips, Mark Stefanelli.

Multiple sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36.

We report a multistage genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage.

The first stage consisted of a genome scan for linkage with 498 microsatellite markers at an average spacing of 7 cM in 219 sibling pairs.

The second stage involved further genotyping of markers from positive regions in an independent sample of 333 affected sibling pairs.

The global distribution of allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group.

This shift indicates that the number of contributing genetic factors is likely to be moderate to large.

Only markers at chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0.

The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33).

Suggestive linkage evidence for a previously reported location on chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated.

We showed that the overall excess allele sharing we observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone.

This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci.

These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.