A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility.
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.
Sawcer
Stephen
S
University of Cambridge Neurology Unit, Addenbrooke's Hospital, Cambridge, UK.
Maranian
Mel
M
Setakis
Efrosini
E
Curwen
Val
V
Akesson
Eva
E
Hensiek
Anke
A
Coraddu
Francesca
F
Roxburgh
Richard
R
Sawcer
David
D
Gray
Julia
J
Deans
Jackie
J
Goodfellow
Peter N
PN
Walker
Neil
N
Clayton
David
D
Compston
Alastair
A
D000328:Adult; D016009:Chi-Square Distribution; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D015894:Genome, Human; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics*; D010865:Pilot Projects
D005819:Genetic Markers