Human Genetics

, Volume 134, Issue 5, pp 459–465 | Cite as

Progress towards the integration of pharmacogenomics in practice

  • Sean D. MooneyEmail author
Review Paper
Part of the following topical collections:
  1. Computational Molecular Medicine


Understanding the role genes and genetic variants play in clinical treatment response continues to be an active area of research with the goal of common clinical use. This goal has developed into today’s industry of pharmacogenomics, where new drug-gene relationships are discovered and further characterized, published and then curated into national and international resources for use by researchers and clinicians. These efforts have given us insight into what a pharmacogenomic variant is, and how it differs from human disease variants and common polymorphisms. While publications continue to reveal pharmacogenomic relationships between genes and specific classes of drugs, many challenges remain toward the goal of widespread use clinically. First, the clinical guidelines for pharmacogenomic testing are still in their infancy. Second, sequencing technologies are changing rapidly making it somewhat unclear what genetic data will be available to the clinician at the time of care. Finally, what and when to return data to a patient is an area under constant debate. New innovations such as PheWAS approaches and whole genome sequencing studies are enabling a tsunami of new findings. In this review, pharmacogenomic variants, pharmacogenomic resources, interpretation clinical guidelines and challenges, such as WGS approaches, and the impact of pharmacogenomics on drug development and regulatory approval are reviewed.


Genome Wide Association Study Warfarin Dose Dose Guideline VKORC1 Gene Study Genome Wide Association Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



SDM is funded by NIH R01 LM009722 (PI:Mooney) and the Buck Trust.


  1. (FDA), T. F. a. D. A. (2013) “Clinical pharmacogenomics: premarket evaluation in early-phase clinical studies and Recommendations for labeling.” from
  2. Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7: Unit7 20Google Scholar
  3. Allison M (2010) Genetic testing clamp down. Nat Biotechnol 28(7):633CrossRefPubMedGoogle Scholar
  4. Ardlie KG, Kruglyak L, Seielstad M (2002) Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 3(4):299–309CrossRefPubMedGoogle Scholar
  5. Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, Dudley JT, Ormond KE, Pavlovic A, Morgan AA, Pushkarev D, Neff NF, Hudgins L, Gong L, Hodges LM, Berlin DS, Thorn CF, Sangkuhl K, Hebert JM, Woon M, Sagreiya H, Whaley R, Knowles JW, Chou MF, Thakuria JV, Rosenbaum AM, Zaranek AW, Church GM, Greely HT, Quake SR, Altman RB (2010) Clinical assessment incorporating a personal genome. Lancet 375(9725):1525–1535CrossRefPubMedCentralPubMedGoogle Scholar
  6. Booth RA, Ansari MT, Loit E, Tricco AC, Weeks L, Doucette S, Skidmore B, Sears M, Sy R, Karsh J (2011) Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review. Ann Intern Med 154(12):814–823 W-295-818CrossRefPubMedGoogle Scholar
  7. Brauch H, Schwab M (2014) Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer. Br J Clin Pharmacol 77(4):695–703CrossRefPubMedCentralPubMedGoogle Scholar
  8. Brooksbank C, Bergman MT, Apweiler R, Birney E, Thornton J (2014) The European Bioinformatics Institute’s data resources 2014. Nucleic Acids Res 42(Database issue):D18–D25CrossRefPubMedCentralPubMedGoogle Scholar
  9. Crowley JJ, Sullivan PF, McLeod HL (2009) Pharmacogenomic genome-wide association studies: lessons learned thus far. Pharmacogenomics 10(2):161–163CrossRefPubMedCentralPubMedGoogle Scholar
  10. Daly AK (2010) Genome-wide association studies in pharmacogenomics. Nat Rev Genet 11(4):241–246CrossRefPubMedGoogle Scholar
  11. Daly AK (2012) Using genome-wide association studies to identify genes important in serious adverse drug reactions. Annu Rev Pharmacol Toxicol 52:21–35CrossRefPubMedGoogle Scholar
  12. Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, Wang D, Masys DR, Roden DM, Crawford DC (2010) PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics 26(9):1205–1210CrossRefPubMedCentralPubMedGoogle Scholar
  13. Denny JC, Bastarache L, Ritchie MD, Carroll RJ, Zink R, Mosley JD, Field JR, Pulley JM, Ramirez AH, Bowton E, Basford MA, Carrell DS, Peissig PL, Kho AN, Pacheco JA, Rasmussen LV, Crosslin DR, Crane PK, Pathak J, Bielinski SJ, Pendergrass SA, Xu H, Hindorff LA, Li R, Manolio TA, Chute CG, Chisholm RL, Larson EB, Jarvik GP, Brilliant MH, McCarty CA, Kullo IJ, Haines JL, Crawford DC, Masys DR, Roden DM (2013) Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat Biotechnol 31(12):1102–1110CrossRefPubMedCentralPubMedGoogle Scholar
  14. Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, Merker JD, Goldfeder RL, Enns GM, David SP, Pakdaman N, Ormond KE, Caleshu C, Kingham K, Klein TE, Whirl-Carrillo M, Sakamoto K, Wheeler MT, Butte AJ, Ford JM, Boxer L, Ioannidis JP, Yeung AC, Altman RB, Assimes TL, Snyder M, Ashley EA, Quertermous T (2014) Clinical interpretation and implications of whole-genome sequencing. JAMA 311(10):1035–1045CrossRefPubMedCentralPubMedGoogle Scholar
  15. Eichelbaum M (2013) Pharmacogenetics: current state after 30 years of research. Dtsch Med Wochenschr 138(13):659–661CrossRefPubMedGoogle Scholar
  16. Eichelbaum M, Ingelman-Sundberg M, Evans WE (2006) Pharmacogenomics and individualized drug therapy. Annu Rev Med 57:119–137CrossRefPubMedGoogle Scholar
  17. Evans WE, McLeod HL (2003) Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 348(6):538–549CrossRefPubMedGoogle Scholar
  18. Garten Y, Tatonetti NP, Altman RB (2010) Improving the prediction of pharmacogenes using text-derived drug-gene relationships. Pac Symp Biocomput: 305–314Google Scholar
  19. Gharani N, Keller MA, Stack CB, Hodges LM, Schmidlen TJ, Lynch DE, Gordon ES, Christman MF (2013) The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system. Genome Med 5(10):93CrossRefPubMedCentralPubMedGoogle Scholar
  20. Giacomini KM, Brett CM, Altman RB, Benowitz NL, Dolan ME, Flockhart DA, Johnson JA, Hayes DF, Klein T, Krauss RM, Kroetz DL, McLeod HL, Nguyen AT, Ratain MJ, Relling MV, Reus V, Roden DM, Schaefer CA, Shuldiner AR, Skaar T, Tantisira K, Tyndale RF, Wang L, Weinshilboum RM, Weiss ST, Zineh I, Pharmacogenetics Research Network (2007) The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther 81(3):328–345CrossRefPubMedGoogle Scholar
  21. Gisbert JP, Gomollon F (2008) Common misconceptions in the diagnosis and management of anemia in inflammatory bowel disease. Am J Gastroenterol 103(5):1299–1307CrossRefPubMedGoogle Scholar
  22. Glubb DM, Paugh SW, van Schaik RH, Innocenti F (2013) A guide to the current Web-based resources in pharmacogenomics. Methods Mol Biol 1015:293–310CrossRefPubMedCentralPubMedGoogle Scholar
  23. Gordon AS, Smith JD, Xiang Q, Metzker ML, Gibbs RA, Mardis ER, Nickerson DA, Fulton RS, Scherer SE (2012). PGRNseq: a new sequencing-based platform for high-throughput pharmacogenomic implementation and discovery. American Society of Human Genetics (ASHG) Annual Meeting, Session 46. Pharmacogenetics: from discovery to implementation, Boston, USAGoogle Scholar
  24. Guo Y, Weller P, Farrell E, Cheung P, Fitch B, Clark D, Wu SY, Wang J, Liao G, Zhang Z, Allard J, Cheng J, Nguyen A, Jiang S, Shafer S, Usuka J, Masjedizadeh M, Peltz G (2006) In silico pharmacogenetics of warfarin metabolism. Nat Biotechnol 24(5):531–536CrossRefPubMedCentralPubMedGoogle Scholar
  25. Guo Y, Lu P, Farrell E, Zhang X, Weller P, Monshouwer M, Wang J, Liao G, Zhang Z, Hu S, Allard J, Shafer S, Usuka J, Peltz G (2007) In silico and in vitro pharmacogenetic analysis in mice. Proc Natl Acad Sci USA 104(45):17735–17740CrossRefPubMedCentralPubMedGoogle Scholar
  26. Hoskins JM, Marcuello E, Altes A, Marsh S, Maxwell T, Van Booven DJ, Paré L, Culverhouse R, McLeod HL, Baiget M (2008) Irinotecan pharmacogenetics: influence of pharmacodynamic genes. Clin Cancer Res 14(6):1788–1796CrossRefPubMedGoogle Scholar
  27. Huang RS, Gamazon ER (2013) Translating pharmacogenomics discoveries into the clinic: an implementation framework. Genome Med 5(10):94CrossRefPubMedCentralPubMedGoogle Scholar
  28. Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5(1):6–13CrossRefPubMedGoogle Scholar
  29. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB, Clinical Pharmacogenetics Implementation Consortium (2011) Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90(4):625–629CrossRefPubMedCentralPubMedGoogle Scholar
  30. Johnson JA, Burkley BM, Langaee TY, Clare-Salzler MJ, Klein TE, Altman RB (2012) Implementing personalized medicine: development of a cost-effective customized pharmacogenetics genotyping array. Clin Pharmacol Ther 92(4):437–439CrossRefPubMedCentralPubMedGoogle Scholar
  31. Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH, Investigators C (2013) A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 369(24):2283–2293CrossRefPubMedCentralPubMedGoogle Scholar
  32. Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE (2013) PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics 23(11):643–647CrossRefPubMedCentralPubMedGoogle Scholar
  33. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42(Database issue):D980–D985CrossRefPubMedCentralPubMedGoogle Scholar
  34. Lee MT, Klein TE (2013) Pharmacogenetics of warfarin: challenges and opportunities. J Hum Genet 58(6):334–338CrossRefPubMedGoogle Scholar
  35. Li B, Seligman C, Thusberg J, Miller JL, Auer J, Whirl-Carrillo M, Capriotti E, Klein TE, Mooney SD (2014) In silico comparative characterization of pharmacogenomic missense variants. BMC Genomics 15(Suppl 4):S4Google Scholar
  36. Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, Mooney SD, Radivojac P (2009) Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25(21):2744–2750CrossRefPubMedCentralPubMedGoogle Scholar
  37. Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J (2010) Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol 69(3):222–230CrossRefPubMedCentralPubMedGoogle Scholar
  38. McCarty CA, Chisholm RL, Chute CG, Kullo IJ, Jarvik GP, Larson EB, Li R, Masys DR, Ritchie MD, Roden DM, Struewing JP, Wolf WA, eMERGE Team (2011) The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies. BMC Med Genomics 4:13CrossRefPubMedCentralPubMedGoogle Scholar
  39. McLeod HL (2013) Cancer pharmacogenomics: early promise, but concerted effort needed. Science 339(6127):1563–1566CrossRefPubMedCentralPubMedGoogle Scholar
  40. Mort M, Sterne-Weiler T, Li B, Ball EV, Cooper DN, Radivojac P, Sanford JR, Mooney SD (2014) MutPred Splice: machine learning-based prediction of exonic variants that disrupt splicing. Genome Biol 15(1):R19CrossRefPubMedCentralPubMedGoogle Scholar
  41. Motsinger-Reif AA, Jorgenson E, Relling MV, Kroetz DL, Weinshilboum R, Cox NJ, Roden DM (2013) Genome-wide association studies in pharmacogenomics: successes and lessons. Pharmacogenet Genomics 23(8):383–394CrossRefPubMedCentralPubMedGoogle Scholar
  42. Nebert DW (1999) Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet 56(4):247–258CrossRefPubMedGoogle Scholar
  43. Neuraz A, Chouchana L, Malamut G, Le Beller C, Roche D, Beaune P, Degoulet P, Burgun A, Loriot MA, Avillach P (2013) Phenome-wide association studies on a quantitative trait: application to TPMT enzyme activity and thiopurine therapy in pharmacogenomics. PLoS Comput Biol 9(12):e1003405CrossRefPubMedCentralPubMedGoogle Scholar
  44. Oetting WS, Robinson PN, Greenblatt MS, Cotton RG, Beck T, Carey JC, Doelken SC, Girdea M, Groza T, Hamilton CM, Hamosh A, Kerner B, MacArthur JA, Maglott DR, Mons B, Rehm HL, Schofield PN, Searle BA, Smedley D, Smith CL, Bernstein IT, Zankl A, Zhao EY (2013) Getting ready for the Human Phenome Project: the 2012 forum of the Human Variome Project. Hum Mutat 34(4):661–666PubMedCentralPubMedGoogle Scholar
  45. Ormond KE, Wheeler MT, Hudgins L, Klein TE, Butte AJ, Altman RB, Ashley EA, Greely HT (2010) Challenges in the clinical application of whole-genome sequencing. Lancet 375(9727):1749–1751CrossRefPubMedGoogle Scholar
  46. Owen RP, Altman RB, Klein TE (2008) PharmGKB and the International Warfarin Pharmacogenetics Consortium: the changing role for pharmacogenomic databases and single-drug pharmacogenetics. Hum Mutat 29(4):456–460CrossRefPubMedGoogle Scholar
  47. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001) Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286(18):2270–2279CrossRefPubMedGoogle Scholar
  48. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M, E.-P. Group (2013) A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 369(24):2294–2303CrossRefPubMedGoogle Scholar
  49. Price MJ, Carson AR, Murray SS, Phillips T, Janel L, Tisch R, Topol E, Levy S (2012) First pharmacogenomic analysis using whole exome sequencing to identify novel genetic determinants of clopidogrel response variability: results of the genotype information and functional testing (gift) exome study. J Am Coll Cardiol 59(13s1):E9CrossRefGoogle Scholar
  50. Pulley JM, Denny JC, Peterson JF, Bernard GR, Vnencak-Jones CL, Ramirez AH, Delaney JT, Bowton E, Brothers K, Johnson K, Crawford DC, Schildcrout J, Masys DR, Dilks HH, Wilke RA, Clayton EW, Shultz E, Laposata M, McPherson J, Jirjis JN, Roden DM (2012) Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin Pharmacol Ther 92(1):87–95CrossRefPubMedCentralPubMedGoogle Scholar
  51. Ramos EM, Din-Lovinescu C, Berg JS, Brooks LD, Duncanson A, Dunn M, Good P, Hubbard TJ, Jarvik GP, O’Donnell C, Sherry ST, Aronson N, Biesecker LG, Blumberg B, Calonge N, Colhoun HM, Epstein RS, Flicek P, Gordon ES, Green ED, Green RC, Hurles M, Kawamoto K, Knaus W, Ledbetter DH, Levy HP, Lyon E, Maglott D, McLeod HL, Rahman N, Randhawa G, Wicklund C, Manolio TA, Chisholm RL, Williams MS (2014) Characterizing genetic variants for clinical action. Am J Med Genet C Semin Med Genet 166(1):93–104CrossRefGoogle Scholar
  52. Relling MV, Klein TE (2011) CPIC: clinical Pharmacogenetics Implementation Consortium of the pharmacogenomics research network. Clin Pharmacol Ther 89(3):464–467CrossRefPubMedCentralPubMedGoogle Scholar
  53. Ritchie MD (2012) The success of pharmacogenomics in moving genetic association studies from bench to bedside: study design and implementation of precision medicine in the post-GWAS era. Hum Genet 131(10):1615–1626CrossRefPubMedCentralPubMedGoogle Scholar
  54. Ritchie GR, Dunham I, Zeggini E, Flicek P (2014) Functional annotation of noncoding sequence variants. Nat Methods 11(3):294–296CrossRefPubMedGoogle Scholar
  55. Ross CJ, Visscher H, Sistonen J, Brunham LR, Pussegoda K, Loo TT, Rieder MJ, Koren G, Carleton BC, Hayden MR, C. Consortium (2010) The Canadian Pharmacogenomics Network for drug safety: a model for safety pharmacology. Thyroid 20(7):681–687CrossRefPubMedGoogle Scholar
  56. Scott SA (2013) Clinical pharmacogenomics: opportunities and challenges at point of care. Clin Pharmacol Ther 93(1):33–35CrossRefPubMedCentralPubMedGoogle Scholar
  57. Sheridan C (2014) Milestone approval lifts Illumina’s NGS from research into clinic. Nat Biotechnol 32(2):111–112CrossRefPubMedGoogle Scholar
  58. Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN (2012) The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformat Chapter 1: Unit1 13Google Scholar
  59. Stergiopoulos K, Brown DL (2014) Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med 174(8):1330–1338CrossRefPubMedGoogle Scholar
  60. Sturm AC, Sweet K, Manickam K (2013) Implementation of a clinical research pharmacogenomics program at an academic medical center: role of the genetics healthcare professional. Pharmacogenomics 14(7):703–706CrossRefPubMedCentralPubMedGoogle Scholar
  61. Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ (2011) Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharmacol Ther 89(5):662–673CrossRefPubMedGoogle Scholar
  62. Thorn CF, Klein TE, Altman RB (2013) PharmGKB: the pharmacogenomics knowledge base. Methods Mol Biol 1015:311–320CrossRefPubMedCentralPubMedGoogle Scholar
  63. Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, Konstantinides S, Le Cessie S, Maltezos E, van der Meer FJ, Redekop WK, Remkes M, Rosendaal FR, van Schie RM, Tavridou A, Tziakas D, Wadelius M, Manolopoulos VG, Maitland-van der Zee AH, E.-P. Group (2013) A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 369(24):2304–2312CrossRefPubMedGoogle Scholar
  64. Wang L, Weinshilboum RM (2008) Pharmacogenomics: candidate gene identification, functional validation and mechanisms. Hum Mol Genet 17(R2):R174–R179CrossRefPubMedCentralPubMedGoogle Scholar
  65. Wheeler HE, Maitland ML, Dolan ME, Cox NJ, Ratain MJ (2013) Cancer pharmacogenomics: strategies and challenges. Nat Rev Genet 14(1):23–34CrossRefPubMedCentralPubMedGoogle Scholar
  66. Zhao Y, Clark WT, Mort M, Cooper DN, Radivojac P, Mooney SD (2011) Prediction of functional regulatory SNPs in monogenic and complex disease. Hum Mutat 32(10):1183–1190CrossRefPubMedCentralPubMedGoogle Scholar
  67. Zineh I, Pacanowski MA (2011) Pharmacogenomics in the assessment of therapeutic risks versus benefits: inside the United States Food and Drug Administration. Pharmacotherapy 31(8):729–735CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Buck Institute for Research on AgingNovatoUSA

Personalised recommendations