Interindividual variability in drug response, ranging from no therapeutic benefit to life-threatening adverse reactions, is influenced by variation in genes that control the absorption, distribution, metabolism and excretion of drugs1. We genotyped 904 single-nucleotide polymorphisms (SNPs) from 55 such genes in two population samples (European and Japanese) and identified a set of tagging SNPs that represents the common variation in these genes, both known and unknown. Extensive empirical evaluations, including a direct assessment of association with candidate functional SNPs in a new, larger population sample, validated the performance of these tagging SNPs and confirmed their utility for linkage-disequilibrium mapping in pharmacogenetics. The analyses also suggest that rare variation is not amenable to tagging strategies.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival
BMC Medicine Open Access 08 September 2008
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Goldstein, D.B., Tate, S.K. & Sisodiya, S.M. Pharmacogenetics goes genomic. Nat. Rev. Genet. 4, 937–947 (2003).
Goldstein, D.B., Ahmadi, K.R., Weale, M.E. & Wood, N.W. Genome scans and candidate gene approaches in the study of common diseases and variable drug responses. Trends Genet. 19, 615–622 (2003).
Weale, M.E. et al. Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. Am. J. Hum. Genet. 73, 551–565 (2003).
Kamatani, N. et al. Large-scale single-nucleotide polymorphism (SNP) and haplotype analyses, using dense SNP maps, of 199 drug-related genes in 752 subjects: the analysis of the association between uncommon SNPs within haplotype blocks and the haplotypes constructed with haplotype-tagging SNPs. Am. J. Hum. Genet. 75, 106–120 (2004).
Pritchard, J.P. & Przeworski, M. Linkage disequilibrium in humans: models and data. Am. J. Hum. Genet. 69, 1–14 (2001).
Chapman, J.M. et al. Detecting disease associations due to linkage disequilibrium: a class of tests and the determinants of statistical power. Hum. Hered. 56, 18–31 (2003).
Carlson, C.S. et al. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am. J. Hum. Genet. 74, 106–120 (2004).
Schulze, T.G. et al. Defining haplotype blocks and tag single-nucleotide polymorphisms in the human genome. Hum. Mol. Genet. 13, 335–342 (2004).
Ke, X. et al. The impact of SNP density on fine-scale patterns of linkage disequilibrium. Hum. Mol. Genet. 13, 577–588 (2004).
Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).
Salisbury, B.A. et al. SNP and haplotype variation in the human genome. Mutat. Res. 526, 53–61 (2003).
Capelli, C. et al. A Y chromosome census of the British Isles. Curr. Biol. 27, 979–984 (2003).
Taylor, J.D. et al. Flow cytometric platform for high-throughput single nucleotide polymorphism analysis. Biotechniques 30, 661–669 (2001).
Qin, Z.S., Niu, T. & Liu, J.S. Partition-ligation-expectation-maximization algorithm for haplotype inference with single nucleotide polymorphisms. Am. J. Hum. Genet. 71, 1242–1247 (2002).
We thank D.H. Smart, T.T. Ashton, S.A. Shouse and B. Zheng for their contributions in bioinformatics, sequencing, SNP discovery and data management. K.R.A. and N.S. were supported by awards from the Leverhulme Trust to D.B.G. A University College London Hospitals trust clinical research and development committee grant to N.W.W. and D.B.G. is acknowledged. D.B.G. holds a Royal Society/Wolfson Research Merit Award.
The authors declare no competing financial interests.
Distribution of minor allele frequencies and marker characteristics for the 55 genes. (PDF 98 kb)
Number of high-LD blocks and percent sequence belonging to high-LD blocks, as a function of block size in the CEPH and the Japanese. (PDF 71 kb)
Initial sample size and performance of tags selected in the full data set. (PDF 90 kb)
Initial sample size and performance of tags selected in the reduced data set (SNPs excluded with MAF < 0.05). (PDF 140 kb)
Comparison of results obtained through bootstrapping (sampling with replacement) and splitting (sampling without replacement). (PDF 91 kb)
SNP-by-SNP performance of the tags selected for each gene or gene complex (SNPs excluded with MAF < 0.05) in the CEPH. (PDF 157 kb)
SNP-by-SNP performance of the tags selected for each gene or gene complex (SNPs excluded with MAF < 0.05) in the Japanese. (PDF 92 kb)
Plot of the minor allele frequency (MAF) of 69 SNPs in 238 individuals from Aberdeen against 64 CEPH individuals. (PDF 65 kb)
The effect of initial genotyping density on tag performance. (PDF 87 kb)
Summary information on all ADME gene clusters. (XLS 68 kb)
Summary information of all 904 SNPs studied as part of this study. (XLS 157 kb)
The tagging SNPs for the CEPH sample. (PDF 71 kb)
The tagging SNPs for the Japanese sample. (PDF 69 kb)
The cosmopolitan tagging SNP set. (PDF 73 kb)
List of the 9 functional variants included in the analyses. (PDF 86 kb)
List of the variants genotyped in 238 individuals from Aberdeen for direct evaluation of the utility of tSNPs. (PDF 60 kb)
The list of genes organized into clusters to quantify the effect of long-range LD. (PDF 48 kb)
The list of genes used in the density experiments. (PDF 46 kb)
About this article
Cite this article
Ahmadi, K., Weale, M., Xue, Z. et al. A single-nucleotide polymorphism tagging set for human drug metabolism and transport. Nat Genet 37, 84–89 (2005). https://doi.org/10.1038/ng1488
This article is cited by
Archives of Toxicology (2022)
The Pharmacogenomics Journal (2013)
The Medical and Economic Roles of Pipeline Pharmacogenetics: Alzheimer's Disease as a Model of Efficacy and HLA-B*5701 as a Model of Safety
The Pharmacogenomics Journal (2009)
Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese
The Pharmacogenomics Journal (2009)