A High-Density Screen for Linkage in Multiple Sclerosis
Open accessAbstract
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.
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Linkage analyses in extended multiple sclerosis affected families validated the HLA association but showed no significant linkage to loci outside the MHC.
“These validated the HLA association but showed no significant linkage to loci outside the MHC.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [24]
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- Authors
- *
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- *
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2005-09
- Volume
- 77
- Issue
- 3
- Pages
- 454-467
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1226210
- OpenAlex
- W114001912
- Cited by
- 297
- References
- 69
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 10 · 2022: 8 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 11 · 2017: 5 · 2016: 10 · 2015: 9 · 2014: 12 · 2013: 9 · 2012: 25
- FWCI
- 23.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Multiple Sclerosis Society
- Wellcome Trust
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (P01AI065687, U19AI067152)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK064869, U01DK062432)
- National Institute of Neurological Disorders and Stroke (NS032830, R01NS032830)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- multiple sclerosis, genetic linkage, high-density genotyping, major histocompatibility complex, chromosome 6p21, chromosome 19p13, multiplex families, susceptibility genes
- MeSH terms
- Australia, Chromosome Mapping, Chromosomes, Human, Europe, Family, Genetic Markers, Genetic Testing, Humans, Genetic Linkage, Middle Aged, Multiple Sclerosis, United States, Genetic Predisposition to Disease, Genomics
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