Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity.
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.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Andrew P
AP
Morris
John C
JC
Whittaker
Chun-Fang
CF
Xu
Louise K
LK
Hosking
David J
DJ
Balding
D001499:Bayes Theorem; D002874:Chromosome Mapping / Q000379:methods*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012984:Software
D019389:Cytochrome P-450 CYP2D6