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Variability in GWAS analysis: the impact of genotype calling algorithm inconsistencies

Abstract

The Genome-Wide Association Working Group (GWAWG) is part of a large-scale effort by the MicroArray Quality Consortium (MAQC) to assess the quality of genomic experiments, technologies and analyses for genome-wide association studies (GWASs). One of the aims of the working group is to assess the variability of genotype calls within and between different genotype calling algorithms using data for coronary artery disease from the Wellcome Trust Case Control Consortium (WTCCC) and the University of Ottawa Heart Institute. Our results show that the choice of genotyping algorithm (for example, Bayesian robust linear model with Mahalanobis distance classifier (BRLMM), the corrected robust linear model with maximum-likelihood-based distances (CRLMM) and CHIAMO (developed and implemented by the WTCCC)) can introduce marked variability in the results of downstream case–control association analysis for the Affymetrix 500K array. The amount of discordance between results is influenced by how samples are combined and processed through the respective genotype calling algorithm, indicating that systematic genotype errors due to computational batch effects are propagated to the list of single-nucleotide polymorphisms found to be significantly associated with the trait of interest. Further work using HapMap samples shows that inconsistencies between Affymetrix arrays and calling algorithms can lead to genotyping errors that influence downstream analysis.

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Acknowledgements

We thank all members of the GWAWG and MAQC for their contribution to this article as well as the members of the WTCCC and Dr George Wells from the University of Ottawa Heart Institute for providing access to the data. We also thank the anonymous reviewers for their invaluable feedback, which has made this paper a much improved contribution.

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Correspondence to K Miclaus.

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Miclaus, K., Chierici, M., Lambert, C. et al. Variability in GWAS analysis: the impact of genotype calling algorithm inconsistencies. Pharmacogenomics J 10, 324–335 (2010). https://doi.org/10.1038/tpj.2010.46

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Keywords

  • genotype calling algorithms
  • BRLMM
  • CRLMM
  • CHIAMO
  • batch effects
  • GWAS
  • association studies

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