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Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity

By Andrew P. Morris, John C. Whittaker, Chun-Fang Xu, Louise K. Hosking and David J. Balding

Abstract

Single-nucleotide polymorphism (SNP) genotypes were recently examined in an 890-kb region flanking the human gene CYP2D6. Single-marker and haplotype-based analyses identified, with genomewide significance (P < 10-7), a 403-kb interval displaying strong linkage disequilibrium (LD) with predicted poor-metabolizer phenotype. However, the width of this interval makes the location of causal variants difficult: for example, the interval contains seven known or predicted genes in addition to CYP2D6. We have developed the Bayesian fine-mapping software coldmap, which, applied to these genotype data, yields a 95% location interval covering only 185 kb and establishes genomewide significance for a causal locus within the region. Strikingly, our interval correctly excludes four SNPs, which individually display association with genomewide significance, including the SNP showing strongest LD (P < 10-34). In addition, coldmap distinguishes homozygous cases for the major CYP2D6 mutation from those bearing minor mutations. We further investigate a selection of SNP subsets and find that previously reported methods lead to a 38% savings in SNPs at the cost of an increase of <20% in the width of the location interval

Topics: Biological Sciences
Publisher: National Academy of Sciences
Year: 2003
DOI identifier: 10.1073/pnas.2235031100
OAI identifier: oai:pubmedcentral.nih.gov:263833
Provided by: PubMed Central
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