Haplotype tagging for the identification of common disease genes

Johnson, Gillian C.L.; Esposito, Laura; Barratt, Bryan J.; Smith, Annabel N.; Heward, Joanne; Di Genova, Gianfranco; Ueda, Hironori; Cordell, Heather J.; Eaves, Iain A.; Dudbridge, Frank; Twells, Rebecca C.J.; Payne, Felicity; Hughes, Wil; Nutland, Sarah; Stevens, Helen; Carr, Phillipa; Tuomilehto-Wolf, Eva; Tuomilehto, Jaakko; Gough, Stephen C.L.; Clayton, David G.; Todd, John A.

doi:10.1038/ng1001-233

Cited by 1,174Genetic Associations and EpidemiologyForensic and Genetic ResearchGenetic Mapping and Diversity in Plants and Animals

Haplotype tagging for the identification of common disease genes

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Johnson, Gillian C.L., Esposito, Laura, Barratt, Bryan J., Smith, Annabel N., Heward, Joanne, Di Genova, Gianfranco, Ueda, Hironori, Cordell, Heather J. +13 more·2001·Nature Genetics

DOI 10.1038/ng1001-233

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Abstract

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

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Nearby variants form a block-like structure consisting of regions with little evidence for historical recombination and limited haplotype diversity; within such regions, genotypes of common SNPs can be inferred from a few empirically determined tag SNPs.
“Nearby variants were observed to form a block-like structure consisting of regions characterized by little evidence for historical recombination and limited haplo-type diversity (44, 45). Within such regions, which soon proved general (46), genotypes of common SNPs could be inferred from knowledge of only a few empirically determined tag SNPs (45–47).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [47]

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Authors: Johnson, G. C. L., Esposito, L., Barratt, B. J., Smith, A. N., Heward, J., Di Genova, G., Ueda, H., Cordell, H. J., Eaves, I. A., Dudbridge, F., Twells, R. C. J., Payne, F., Hughes, W., Nutland, S., Stevens, H., Carr, P., Tuomilehto-Wolf, E., Tuomilehto, J., Gough, S. C. L., Clayton, D. G., & Todd, J. A.
Affiliations: University of Cambridge (GB)
Heartlands Hospital (GB)
University of Helsinki (FI)
Corresponding author: Todd, John A.
ORCID: Esposito, Laura
Barratt, Bryan J.
Ueda, Hironori
Cordell, Heather J.
Dudbridge, Frank
Payne, Felicity
Tuomilehto, Jaakko
Clayton, David G.
Todd, John A.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2001-10
Volume: 29
Issue: 2
Pages: 233-237
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng1001-233
OpenAlex: W1583476286
Cited by: 1,174
References: 32
Citations by year: 2026: 3 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 13 · 2018: 5 · 2017: 16 · 2016: 10 · 2015: 11 · 2014: 18 · 2013: 22 · 2012: 31
FWCI: 68.93
Type: journal article
Language: en
Open access: green
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion, public-domain)
PubMed (publishedVersion)
ePrints Soton (University of Southampton) (submittedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Newcastle University ePrints (Newcastle Univesity)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords: haplotype tagging, association mapping, single nucleotide polymorphisms, genotyping cost reduction, fine mapping, European populations, resequencing
MeSH terms: Base Sequence, DNA, Haplotypes, Humans, Sequence Homology, Nucleic Acid, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide

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Haplotype tagging for the identification of common disease genes

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