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Assessment of variability in GWAS with CRLMM genotyping algorithm on WTCCC coronary artery disease

The Pharmacogenomics Journal volume 10, pages 347–354 (2010)Cite this article

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Abstract

The robustness of genome-wide association study (GWAS) results depends on the genotyping algorithms used to establish the association. This paper initiated the assessment of the impact of the Corrected Robust Linear Model with Maximum Likelihood Classification (CRLMM) genotyping quality on identifying real significant genes in a GWAS with large sample sizes. With microarray image data from the Wellcome Trust Case–Control Consortium (WTCCC), 1991 individuals with coronary artery disease (CAD) and 1500 controls, genetic associations were evaluated under various batch sizes and compositions. Experimental designs included different batch sizes of 250, 350, 500, 2000 samples with different distributions of cases and controls in each batch with either randomized or simply combined (4:3 case–control ratios) or separate case–control samples as well as whole 3491 samples. The separate composition could create 2–3% discordance in the single nucleotide polymorphism (SNP) results for quality control/statistical analysis and might contribute to the lack of reproducibility between GWAS. CRLMM shows high genotyping accuracy and stability to batch effects. According to the genotypic and allelic tests (P<5.0 × 10−7), nine significant signals on chromosome 9 were found consistently in all batch sizes with combined design. Our findings are critical to optimize the reproducibility of GWAS and confirm the genetic role in the pathophysiology of CAD.

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Acknowledgements

We thank the Wellcome Trust Case–Control Consortium (WTCCC), UK, for providing us the original Affymetix 500 data with CAD patients and controls. We thank Benilton Carvalho and Rafael A Irizarry (Johns Hopkins University) for providing us advice on setting up CRLMM on our computer server. The views presented in this article do not necessarily reflect those of the US Food and Drug Administration.

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Authors and Affiliations

  1. Genomics Group, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA

    L Zhang, S Yin & F Goodsaid

  2. SAS Institute, Cary, NC, USA

    K Miclaus & R D Wolfinger

  3. Fondazione Bruno Kessler, Trento, Italy

    M Chierici & C Furlanello

  4. Health Solutions Group, Microsoft (formerly Rosetta Biosoftware), Redmond, WA, USA

    S Vega

  5. Golden Helix, Bozeman, MT, USA

    C Lambert

  6. National Center for Toxicological Research, FDA, Jefferson, AR, USA

    H Hong

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  1. L Zhang
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  2. S Yin
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  5. S Vega
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Correspondence to F Goodsaid.

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The authors declare no conflict of interest.

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Zhang, L., Yin, S., Miclaus, K. et al. Assessment of variability in GWAS with CRLMM genotyping algorithm on WTCCC coronary artery disease. Pharmacogenomics J 10, 347–354 (2010). https://doi.org/10.1038/tpj.2010.27

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  • DOI: https://doi.org/10.1038/tpj.2010.27

Keywords

  • CRLMM
  • GWAS
  • WTCCC
  • CAD
  • robustness
  • accuracy

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