Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity.
Morris, Andrew P;
Whittaker, John C;
Xu, Chun-Fang;
Hosking, Louise K;
Balding, David J;
(2003)
Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity.
Proceedings of the National Academy of Sciences of the United States of America, 100 (23).
pp. 13442-13446.
ISSN 0027-8424
DOI: https://doi.org/10.1073/pnas.2235031100
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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.
