title: A high-density screen for linkage in multiple sclerosis.
abstract: 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.
authors.affiliation: University of Cambridge, Department of Clinical Neuroscience, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. sjs1016@mole.bio.cam.ac.uk
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.forename: Mel
authors.initials: M
authors.lastname: Maranian
authors.forename: Tai Wai
authors.initials: TW
authors.lastname: Yeo
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Emily
authors.initials: E
authors.lastname: Walsh
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivinson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rimmler
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Silke
authors.initials: S
authors.lastname: Schmidt
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Eva
authors.initials: E
authors.lastname: Akesson
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.forename: Pameli
authors.initials: P
authors.lastname: Datta
authors.forename: Annette
authors.initials: A
authors.lastname: Oturai
authors.forename: Lars P
authors.initials: LP
authors.lastname: Ryder
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
authors.forename: Anne
authors.initials: A
authors.lastname: Spurkland
authors.forename: Kjell-Morten
authors.initials: KM
authors.lastname: Myhr
authors.forename: Mikko
authors.initials: M
authors.lastname: Laaksonen
authors.forename: David
authors.initials: D
authors.lastname: Booth
authors.forename: Robert
authors.initials: R
authors.lastname: Heard
authors.forename: Graeme
authors.initials: G
authors.lastname: Stewart
authors.forename: Robin
authors.initials: R
authors.lastname: Lincoln
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Kenealy
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
mesh_terms: 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
chemical_list: D005819:Genetic Markers