A single-nucleotide polymorphism tagging set for human drug metabolism and transport

ABSTRACT 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. Access through your institution Buy or subscribe This is a preview of subscription

content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue

Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL

ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS STRUCTURAL VARIATION OF THE CODING AND

NON-CODING HUMAN PHARMACOGENOME Article Open access 08 September 2023 PHARMACOGENETIC ANALYSIS OF STRUCTURAL VARIATION IN THE 1000 GENOMES PROJECT USING WHOLE GENOME SEQUENCES Article Open

access 01 October 2024 A CALL FOR INCREASED INCLUSIVITY AND GLOBAL REPRESENTATION IN PHARMACOGENETIC TESTING Article Open access 22 February 2024 REFERENCES * Goldstein, D.B., Tate, S.K.

& Sisodiya, S.M. Pharmacogenetics goes genomic. _Nat. Rev. Genet._ 4, 937–947 (2003). Article  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * 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). Article 

CAS  Google Scholar  * 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). Article  Google

Scholar  * Pritchard, J.P. & Przeworski, M. Linkage disequilibrium in humans: models and data. _Am. J. Hum. Genet._ 69, 1–14 (2001). Article  CAS  Google Scholar  * 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). Article  Google Scholar  * 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). Article

  CAS  Google Scholar  * Schulze, T.G. et al. Defining haplotype blocks and tag single-nucleotide polymorphisms in the human genome. _Hum. Mol. Genet._ 13, 335–342 (2004). Article  CAS 

Google Scholar  * Ke, X. et al. The impact of SNP density on fine-scale patterns of linkage disequilibrium. _Hum. Mol. Genet._ 13, 577–588 (2004). Article  CAS  Google Scholar  * Gabriel,

S.B. et al. The structure of haplotype blocks in the human genome. _Science_ 296, 2225–2229 (2002). Article  CAS  Google Scholar  * Salisbury, B.A. et al. SNP and haplotype variation in the

human genome. _Mutat. Res._ 526, 53–61 (2003). Article  CAS  Google Scholar  * Capelli, C. et al. A Y chromosome census of the British Isles. _Curr. Biol._ 27, 979–984 (2003). Article 

Google Scholar  * Taylor, J.D. et al. Flow cytometric platform for high-throughput single nucleotide polymorphism analysis. _Biotechniques_ 30, 661–669 (2001). Article  CAS  Google Scholar 

* 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). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS 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. AUTHOR INFORMATION Author notes * Kourosh R Ahmadi and Mike E Weale: These

authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Biology (Galton Lab), University College London, The Darwin Building, Gower Street, London, WC1E 6BT, UK

Kourosh R Ahmadi, Mike E Weale, Nicole Soranzo & David B Goldstein * Genetics Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, PO Box 13398, 27709, North Carolina,

USA Zhengyu Y Xue, David P Yarnall, James D Briley, Nigel K Spurr, Daniel K Burns, Allen D Roses & Ann M Saunders * Genetics Research, Tsukuba Research Laboratories, GlaxoSmithKline,

Wadai 43, Tsukuba, Ibaraki, 300-4247, Japan Yuka Maruyama & Mikiro Kobayashi * Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, WC1N 3BG, UK Nicholas W

Wood Authors * Kourosh R Ahmadi View author publications You can also search for this author inPubMed Google Scholar * Mike E Weale View author publications You can also search for this

author inPubMed Google Scholar * Zhengyu Y Xue View author publications You can also search for this author inPubMed Google Scholar * Nicole Soranzo View author publications You can also

search for this author inPubMed Google Scholar * David P Yarnall View author publications You can also search for this author inPubMed Google Scholar * James D Briley View author

publications You can also search for this author inPubMed Google Scholar * Yuka Maruyama View author publications You can also search for this author inPubMed Google Scholar * Mikiro

Kobayashi View author publications You can also search for this author inPubMed Google Scholar * Nicholas W Wood View author publications You can also search for this author inPubMed Google

Scholar * Nigel K Spurr View author publications You can also search for this author inPubMed Google Scholar * Daniel K Burns View author publications You can also search for this author

inPubMed Google Scholar * Allen D Roses View author publications You can also search for this author inPubMed Google Scholar * Ann M Saunders View author publications You can also search for

this author inPubMed Google Scholar * David B Goldstein View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to David B

Goldstein. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIG. 1 Distribution of minor allele

frequencies and marker characteristics for the 55 genes. (PDF 98 kb) SUPPLEMENTARY FIG. 2 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) SUPPLEMENTARY FIG. 3 Initial sample size and performance of tags selected in the full data set. (PDF 90 kb) SUPPLEMENTARY FIG. 4 Initial sample

size and performance of tags selected in the reduced data set (SNPs excluded with MAF < 0.05). (PDF 140 kb) SUPPLEMENTARY FIG. 5 Comparison of results obtained through bootstrapping

(sampling with replacement) and splitting (sampling without replacement). (PDF 91 kb) SUPPLEMENTARY FIG. 6 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) SUPPLEMENTARY FIG. 7 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) SUPPLEMENTARY FIG. 8 Plot of the minor allele frequency (MAF) of 69 SNPs in 238 individuals from Aberdeen against 64 CEPH individuals. (PDF 65 kb) SUPPLEMENTARY

FIG. 9 The effect of initial genotyping density on tag performance. (PDF 87 kb) SUPPLEMENTARY TABLE 1 Summary information on all ADME gene clusters. (XLS 68 kb) SUPPLEMENTARY TABLE 2 Summary

information of all 904 SNPs studied as part of this study. (XLS 157 kb) SUPPLEMENTARY TABLE 3 The tagging SNPs for the CEPH sample. (PDF 71 kb) SUPPLEMENTARY TABLE 4 The tagging SNPs for

the Japanese sample. (PDF 69 kb) SUPPLEMENTARY TABLE 5 The cosmopolitan tagging SNP set. (PDF 73 kb) SUPPLEMENTARY TABLE 6 List of the 9 functional variants included in the analyses. (PDF 86

kb) SUPPLEMENTARY TABLE 7 List of the variants genotyped in 238 individuals from Aberdeen for direct evaluation of the utility of tSNPs. (PDF 60 kb) SUPPLEMENTARY TABLE 8 The list of genes

organized into clusters to quantify the effect of long-range LD. (PDF 48 kb) SUPPLEMENTARY TABLE 9 The list of genes used in the density experiments. (PDF 46 kb) RIGHTS AND PERMISSIONS

Reprints and permissions 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 Download citation * Received: 24 August 2004 * Accepted: 19 November 2004 * Published: 19 December 2004 * Issue Date: 01 January

2005 * DOI: https://doi.org/10.1038/ng1488 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative