A high-density screen for linkage in multiple sclerosis.
To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.
Sawcer
Stephen
S
University of Cambridge, Department of Clinical Neuroscience, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. sjs1016@mole.bio.cam.ac.uk
Ban
Maria
M
Maranian
Mel
M
Yeo
Tai Wai
TW
Compston
Alastair
A
Kirby
Andrew
A
Daly
Mark J
MJ
De Jager
Philip L
PL
Walsh
Emily
E
Lander
Eric S
ES
Rioux
John D
JD
Hafler
David A
DA
Ivinson
Adrian
A
Rimmler
Jacqueline
J
Gregory
Simon G
SG
Schmidt
Silke
S
Pericak-Vance
Margaret A
MA
Akesson
Eva
E
Hillert
Jan
J
Datta
Pameli
P
Oturai
Annette
A
Ryder
Lars P
LP
Harbo
Hanne F
HF
Spurkland
Anne
A
Myhr
Kjell-Morten
KM
Laaksonen
Mikko
M
Booth
David
D
Heard
Robert
R
Stewart
Graeme
G
Lincoln
Robin
R
Barcellos
Lisa F
LF
Hauser
Stephen L
SL
Oksenberg
Jorge R
JR
Kenealy
Shannon J
SJ
Haines
Jonathan L
JL
D001315:Australia; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics*; D005060:Europe; D005190:Family; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D023281:Genomics / Q000379:methods; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D014481:United States
D005819:Genetic Markers