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

AP Morris, JC Whittaker, CF Xu… - Proceedings of the …, 2003 - National Acad Sciences
AP Morris, JC Whittaker, CF Xu, LK Hosking, DJ Balding
Proceedings of the National Academy of Sciences, 2003National Acad Sciences
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 …
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.
National Acad Sciences