Original Article

Application of principal component analysis to pharmacogenomic studies in Canada

  • The Pharmacogenomics Journal (2009) 9, 362372 (2009)
  • doi:10.1038/tpj.2009.36
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Abstract

Ethnicity can confound results in pharmacogenomic studies. Allele frequencies of loci that influence drug metabolism can vary substantially between different ethnicities and underlying ancestral genetic differences can lead to spurious findings in pharmacogenomic association studies. We evaluated the application of principal component analysis (PCA) in a pharmacogenomic study in Canada to detect and correct for genetic ancestry differences using genotype data from 2094 loci in 220 key drug biotransformation genes. Using 89 Coriell worldwide reference samples, we observed a strong correlation between principal component values and geographic origin. We further applied PCA to accurately infer the genetic ancestry in our ethnically diverse Canadian cohort of 524 patients from the GATC study of severe adverse drug reactions. We show that PCA can be successfully applied in pharmacogenomic studies using a limited set of markers to detect underlying differences in genetic ancestry thereby maximizing power and minimizing false-positive findings.

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Acknowledgements

We thank the patients and their families for their participation in the GATC project. We acknowledge the support of the GATC active ADR surveillance network, particularly the site investigators Cheri Nijssen-Jordan, David Johnson, Kevin Hall, Michael Rieder, Shinya Ito, Gideon Koren, Regis Vaillancourt, Pat Elliott-Miller, Jean-Francois Bussières, Denis Lebel, Margaret Murray, Darlene Boliver, Carol Portwine; site surveillance clinicians Linda Verbeek, Rick Kaczowka, Shanna Chan, Becky Malkin, Facundo Garcia, Miho Inoue, Sachi Sakaguchi, Toshihiro Tanaka, Elaine Wong, Brenda Wilson, Pierre Barret, Carol-anne Osborne, Amy Cranston; and research staff at POPI and the CMMT: Anne Smith, Claudette Hildebrand; Lucila Castro, Reza Ghannadan, Catherine Carter, Fudan Miao, Terry Pape and Graeme Honeyman. The study was funded by the Genome Canada, and additional funding was also provided by the Genome British Columbia; the Child & Family Research Institute (Vancouver, BC); the Canadian Institutes of Health Research; Faculties of Pharmaceutical Sciences and Medicine, University of British Columbia; University of Western Ontario; the Canada Gene Cure Foundation; the Canadian Society of Clinical Pharmacology; C17 Research Network: the Childhood Cancer Foundation, Candlelighters Canada; the Canadian Paediatric Society, Merck Frosst; Janssen-Ortho; Illumina; IBM; Eli Lilly; and Pfizer. HV is supported by a postdoctoral research fellowship award from the Michael Smith Foundation for Health Research and the Child and Family Research Institute.

Author information

Affiliations

  1. Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    • H Visscher
    • , C J D Ross
    •  & M R Hayden
  2. Montreal Heart Institute Research Centre and Université de Montreal, Montreal, Quebec, Canada

    • M-P Dubé
    • , A M K Brown
    •  & M S Phillips
  3. Montreal Heart Institute and Genome Québec Pharmacogenomics Centre, Montreal, Quebec, Canada

    • A M K Brown
    •  & M S Phillips
  4. Pharmaceutical Outcomes and Policy Innovations Programme, Department of Paediatrics and Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    • B C Carleton

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Corresponding author

Correspondence to M R Hayden.

Supplementary information

Glossary

PCA

principal component analysis

GWAS

genome-wide association study

ADR

adverse drug reaction

SNP

single nucleotide polymorphism

GATC

genotype-specific approaches to therapy in children