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PMID: 16080120 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A high-density screen for linkage in multiple sclerosis.

American journal of human genetics ·Vol. 77 ·No. 3 ·2005-09-00 ·Pages 454-67

Sawcer S, Ban M, Maranian M, Yeo TW, Compston A, Kirby A, Daly MJ, De Jager PL, Walsh E, Lander ES, Rioux JD, Hafler DA, Ivinson A, Rimmler J, Gregory SG, Schmidt S, Pericak-Vance MA, Akesson E, Hillert J, Datta P, Oturai A, Ryder LP, Harbo HF, Spurkland A, Myhr KM, Laaksonen M, Booth D, Heard R, Stewart G, Lincoln R, Barcellos LF, Hauser SL, Oksenberg JR, Kenealy SJ, Haines JL, International Multiple Sclerosis Genetics Consortium

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.

MeSH Terms
Australia Chromosome Mapping Chromosomes, Human/genetics Europe Family Genetic Linkage Genetic Markers/genetics Genetic Predisposition to Disease/genetics Genetic Testing/methods Genomics/methods Humans Middle Aged Multiple Sclerosis/genetics United States
Chemicals
Genetic Markers
Authors & Affiliations
36 authors, click to expand affiliations / ORCID
Sawcer Stephen
University of Cambridge, Department of Clinical Neuroscience, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. [email protected]
Ban Maria
Maranian Mel
Yeo Tai Wai
Compston Alastair
Kirby Andrew
Daly Mark J
De Jager Philip L
Walsh Emily
Lander Eric S
Rioux John D
Hafler David A
Ivinson Adrian
Rimmler Jacqueline
Gregory Simon G
Schmidt Silke
Pericak-Vance Margaret A
Akesson Eva
Hillert Jan
Datta Pameli
Oturai Annette
Ryder Lars P
Harbo Hanne F
Spurkland Anne
Myhr Kjell-Morten
Laaksonen Mikko
Booth David
Heard Robert
Stewart Graeme
Lincoln Robin
Barcellos Lisa F
Hauser Stephen L
Oksenberg Jorge R
Kenealy Shannon J
Haines Jonathan L
International Multiple Sclerosis Genetics Consortium
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/444547
Email
[email protected]
Published
2005-09-00
Epub
2005-00-29
Pages
454-67
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1226210
Subset
IM
Grants
NIDDK NIH HHS · U01 DK062432 · United States
NIDDK NIH HHS · R01 DK064869 · United States
NIAID NIH HHS · P01 AI065687 · United States
NINDS NIH HHS · NS032830 · United States
NINDS NIH HHS · R01 NS032830 · United States
Wellcome Trust · United Kingdom
NIAID NIH HHS · U19 AI067152 · United States
External Links
PubMed source DOI: 10.1086/444547 PMC Full Text View journal details
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