Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Genome-wide association studies in pharmacogenomics

Nature Reviews Genetics volume 11, pages 241–246 (2010)Cite this article

Subjects

Abstract

Genome-wide association (GWA) studies for pharmacogenomics-related traits are increasingly being performed to identify loci that affect either drug response or susceptibility to adverse drug reactions. Until now, only the largest effects have been detected, partly because of the challenges of obtaining large numbers of cases for pharmacogenomic studies. Since 2007, a range of pharmacogenomics GWA studies have been published that have identified several interesting and novel associations between drug responses or reactions and clinically relevant loci, showing the value of this approach.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Meyer, U. A. Pharmacogenetics — five decades of therapeutic lessons from genetic diversity. Nature Rev. Genet. 5, 669–676 (2004).

    Article  CAS  Google Scholar 

  2. Daly, A. K. Pharmacogenomics of anticoagulants: steps toward personal dosage. Genome Med. 1, 10 (2009).

    Article  Google Scholar 

  3. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).

    Article  CAS  Google Scholar 

  4. Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-a and ribavirin therapy. Nature Genet. 41, 1100–1104 (2009).

    Article  CAS  Google Scholar 

  5. Tanaka, Y. et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nature Genet. 41, 1105–1109 (2009).

    Article  CAS  Google Scholar 

  6. Shuldiner, A. R. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302, 849–857 (2009).

    Article  CAS  Google Scholar 

  7. Cooper, G. M. et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 112, 1022–1027 (2008).

    Article  CAS  Google Scholar 

  8. Takeuchi, F. et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 5, e1000433 (2009).

    Article  Google Scholar 

  9. Teichert, M. et al. A genome-wide association study of acenocoumarol maintenance dosage. Hum. Mol. Genet. 18, 3758–3768 (2009).

    Article  CAS  Google Scholar 

  10. Link, E. et al. SLCO1B1 variants and statin-induced myopathy — a genomewide study. N. Engl. J. Med. 359, 789–799 (2008).

    Article  CAS  Google Scholar 

  11. Daly, A. K. et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genet. 41, 816–819 (2009).

    Article  CAS  Google Scholar 

  12. Eichelbaum, M., Ingelman-Sundberg, M. & Evans, W. E. Pharmacogenomics and individualized drug therapy. Annu. Rev. Med. 57, 119–137 (2006).

    Article  CAS  Google Scholar 

  13. Kweekel, D., Guchelaar, H. J. & Gelderblom, H. Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat. Rev. 34, 656–669 (2008).

    Article  CAS  Google Scholar 

  14. Naisbitt, D. J. et al. Characterization of drug-specific T cells in lamotrigine hypersensitivity. J. Allergy Clin. Immunol. 111, 1393–1403 (2003).

    Article  CAS  Google Scholar 

  15. Mallal, S. et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 359, 727–732 (2002).

    Article  CAS  Google Scholar 

  16. Mallal, S. et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008).

    Article  Google Scholar 

  17. Seeringer, A. & Kirchheiner, J. Pharmacogenetics-guided dose modifications of antidepressants. Clin. Lab. Med. 28, 619–626 (2008).

    Article  Google Scholar 

  18. Kirchheiner, J. et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr. Scand. 104, 173–192 (2001).

    Article  CAS  Google Scholar 

  19. Hulot, J. S. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108, 2244–2247 (2006).

    Article  CAS  Google Scholar 

  20. Simon, T. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med. 360, 363–375 (2009).

    Article  CAS  Google Scholar 

  21. Collet, J. P. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373, 309–317 (2009).

    Article  CAS  Google Scholar 

  22. Schroth, W. et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 302, 1429–1436 (2009).

    Article  CAS  Google Scholar 

  23. Hoskins, J. M., Carey, L. A. & McLeod, H. L. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nature Rev. Cancer 9, 576–586 (2009).

    Article  CAS  Google Scholar 

  24. Roden, D. M. et al. Pharmacogenomics: challenges and opportunities. Ann. Intern. Med. 145, 749–757 (2006).

    Article  Google Scholar 

  25. Liu, C. et al. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol. Med. 14, 575–581 (2008).

    Article  CAS  Google Scholar 

  26. Lavedan, C. et al. Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol. Psychiatry 14, 804–819 (2009).

    Article  CAS  Google Scholar 

  27. Caldwell, M. D. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 111, 4106–4112 (2008).

    Article  CAS  Google Scholar 

  28. Zhang, J. E. et al. Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy. Pharmacogenet. Genomics 19, 781–789 (2009).

    Article  CAS  Google Scholar 

  29. Borgiani, P. et al. CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics 10, 261–266 (2009).

    Article  CAS  Google Scholar 

  30. Thijssen, H. H., Flinois, J.-P. & Beaune, P. H. Cytochrome P450 2C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab. Dispos. 28, 1284–1290 (2000).

    CAS  PubMed  Google Scholar 

  31. de Morais, S. M. F. et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J. Biol. Chem. 269, 15419–15422 (1994).

    CAS  PubMed  Google Scholar 

  32. Iadonato, S. P. & Katze, M. G. Genomics: hepatitis C virus gets personal. Nature 461, 357–358 (2009).

    Article  CAS  Google Scholar 

  33. Becquemont, L. Pharmacogenomics of adverse drug reactions: practical applications and perspectives. Pharmacogenomics 10, 961–969 (2009).

    Article  CAS  Google Scholar 

  34. Wilke, R. A. et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nature Rev. Drug Discov. 6, 904–916 (2007).

    Article  CAS  Google Scholar 

  35. Niemi, M. Transporter pharmacogenetics and statin toxicity. Clin. Pharmacol. Ther. 87, 130–133 (2010).

    Article  CAS  Google Scholar 

  36. Voora, D. et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J. Am. Coll. Cardiol. 54, 1609–1616 (2009).

    Article  CAS  Google Scholar 

  37. Trevino, L. R. et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J. Clin. Oncol. 27, 5972–5978 (2009).

    Article  CAS  Google Scholar 

  38. Donaldson, P. T. et al. Flucloxacillin-induced liver injury: the extended MHC 57.1 haplotype as a major risk factor. Hepatology 48 (Suppl. 1), 396–397 (2008).

    Google Scholar 

  39. Kindmark, A. et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 8, 186–195 (2008).

    Article  CAS  Google Scholar 

  40. Khan, A. A. et al. Bisphosphonate associated osteonecrosis of the jaw. J. Rheumatol. 36, 478–490 (2009).

    Article  Google Scholar 

  41. Sarasquete, M. E. et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 112, 2709–2712 (2008).

    Article  CAS  Google Scholar 

  42. Totah, R. A. & Rettie, A. E. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin. Pharmacol. Ther. 77, 341–52 (2005).

    Article  CAS  Google Scholar 

  43. Fleming, I. Cytochrome P450 epoxygenases as EDHF synthase(s). Pharmacol. Res. 49, 525–533 (2004).

    Article  CAS  Google Scholar 

  44. Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009).

    Article  CAS  Google Scholar 

  45. Strausberg, R. L., Levy, S. & Rogers, Y. H. Emerging DNA sequencing technologies for human genomic medicine. Drug Discov. Today 13, 569–577 (2008).

    Article  CAS  Google Scholar 

  46. Paulussen, A. D. et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J. Mol. Med. 82, 182–188 (2004).

    Article  CAS  Google Scholar 

  47. McCarthy, M. I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet. 9, 356–369 (2008).

    Article  CAS  Google Scholar 

  48. Byun, E. et al. Genome-wide pharmacogenomic analysis of the response to interferon β therapy in multiple sclerosis. Arch. Neurol. 65, 337–344 (2008).

    Article  Google Scholar 

  49. Turner, S. T. et al. Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension 52, 359–365 (2008).

    Article  CAS  Google Scholar 

  50. Mick, E., Neale, B., Middleton, F. A., McGough, J. J. & Faraone, S. V. Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1412–1418 (2008).

    Article  CAS  Google Scholar 

  51. Yang, J. J. et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301, 393–403 (2009).

    Article  CAS  Google Scholar 

  52. Ising, M. et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch. Gen. Psychiatry 66, 966–975 (2009).

    Article  CAS  Google Scholar 

  53. Garriock, H. A. et al. A genomewide association study of citalopram response in major depressive disorder. Biol. Psychiatry 67, 133–138 (2010).

    Article  CAS  Google Scholar 

  54. Hartford, C. et al. Genome scan implicates adhesion biological pathways in secondary leukemia. Leukemia 21, 2128–2136 (2007).

    Article  CAS  Google Scholar 

  55. Inada, T. et al. Pathway-based association analysis of genome-wide screening data suggest that genes associated with the γ-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. Pharmacogenet. Genomics 18, 317–323 (2008).

    Article  CAS  Google Scholar 

  56. Volpi, S. et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. Mol. Psychiatry 14, 1024–1031 (2009).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Ann K. Daly is at the Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. a.k.daly@ncl.ac.uk,

    Ann K. Daly

Authors
  1. Ann K. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Ann K. Daly's homepage

Nature Reviews Genetics series on genome-wide association studies

Glossary

Abacavir

Reverse transcriptase inhibitor used in the treatment of HIV.

Additive model

A genetic model with an increased disease risk of r for heterozygous genotypes and 2r for homozygous variant genotypes.

Cholestatic hepatitis

Obstruction of bile secretion and dysfunction of bile canaliculi together with inflammation of the liver. There are a number of possible causes, including exposure to certain drugs.

Drug disposition

(Also known as pharmacokinetics.) The process by which a drug is handled by the body following administration. It includes the processes of absorption, distribution, metabolism and excretion of a drug.

Drug metabolism

The biochemical modification or degradation of drugs through specialized enzymatic systems; examples include the cytochrome P450 oxidases and the uridine diphosphate glucuronosyltransferases. The rate of drug metabolism is an important determinant of the duration and intensity of the pharmacological action of drugs.

Drug response

The way an individual patient or cell responds to drug administration. It can be assessed in different ways, either qualitatively or quantitatively depending on the particular drug. The term pharmacodynamics can also be used to describe patient response.

Class I human leukocyte antigen genes

Genes within the human major histocompatibility complex that encode polymorphic membrane glycoproteins that are expressed on all nucleated cells. They form complexes with antigenic peptides and present them to cytotoxic T cells.

Linkage disequilibrium

The non-random association of alleles. For example, alleles of SNPs that reside near one another on a chromosome often occur in non-random combinations owing to infrequent recombination. Linkage disequilibrium is useful in genome-wide association studies as it reduces the number of SNPs that must be interrogated to determine genotypes across the genome. Conversely, strong linkage disequilibrium can complicate the identification of functional variants.

Multivariate regression analysis

Regression analysis includes any technique for modelling and analysing several variables when the focus is on the relationship between a dependent variable (y) and one or more independent variables (x). In multivariate regression analysis, two or more dependent variables are included in one analysis.

Neutropenia

An abnormally low number of neutrophils, the most important type of white blood cell, in the blood.

Odds ratio

A measurement of association that is commonly used in case–control studies. It is defined as the odds of exposure to the susceptible genetic variant in cases compared with the odds of exposure in controls. If the odds ratio is significantly greater than one, the genetic variant is associated with the disease.

Phase III clinical trials

Randomized, controlled, multicentre trials on large patient groups that aim to assess the effectiveness of a new drug under development compared with the current best treatment.

Replication cohort

In the context of a genome-wide association study, a cohort of cases and controls that is drawn from a population comparable to the original population and that is analysed to test the validity of the initial association.

Simvastatin

A particular statin drug. Statins are prescribed to decrease blood cholesterol level. They act by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase.

Sinusoidal

Hepatocytes are polarized cells: one plasma membrane face points towards the sinusoids, or local blood vessels, in the liver and the other face points towards the bile canaliculi. Drugs and other compounds are normally transported into the hepatocyte from the general circulation across the sinusoidal membrane.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daly, A. Genome-wide association studies in pharmacogenomics. Nat Rev Genet 11, 241–246 (2010). https://doi.org/10.1038/nrg2751

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2751

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing