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 predic...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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2003
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| _version_ | 1797100571224702976 |
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| author | Morris, A Whittaker, J Xu, C Hosking, L Balding, D |
| author_facet | Morris, A Whittaker, J Xu, C Hosking, L Balding, D |
| author_sort | Morris, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T05:39:25Z |
| format | Journal article |
| id | oxford-uuid:e50b9db0-f699-4cbe-ab1d-515b2a080571 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:39:25Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:e50b9db0-f699-4cbe-ab1d-515b2a0805712022-03-27T10:21:06ZMultipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e50b9db0-f699-4cbe-ab1d-515b2a080571EnglishSymplectic Elements at Oxford2003Morris, AWhittaker, JXu, CHosking, LBalding, DSingle-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. |
| spellingShingle | Morris, A Whittaker, J Xu, C Hosking, L Balding, D Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity. |
| title | Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity. |
| title_full | Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity. |
| title_fullStr | Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity. |
| title_full_unstemmed | Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity. |
| title_short | Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity. |
| title_sort | multipoint linkage disequilibrium mapping narrows location interval and identifies mutation heterogeneity |
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