One thousand genomes imputation in the national cancer institute breast and prostate cancer cohort consortium aggressive prostate cancer genome-wide association study

Authors

  • Mitchell J. Machiela,

    1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
    2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Constance Chen,

    1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
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  • Liming Liang,

    1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
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  • W. Ryan Diver,

    1. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
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  • Victoria L. Stevens,

    1. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
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  • Konstantinos K. Tsilidis,

    1. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
    2. Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
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  • Christopher A. Haiman,

    1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Stephen J. Chanock,

    1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • David J. Hunter,

    1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
    2. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
    3. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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  • Peter Kraft,

    Corresponding author
    1. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
    • 655 Huntington Avenue, Building II Room 207, Boston, Massachusetts 02115.
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  • on behalf of the National Cancer Institute Breast and Prostate Cancer Cohort Consortium


  • The authors report no conflicts of interest.

Abstract

BACKGROUND

Genotype imputation substantially increases available markers for analysis in genome-wide association studies (GWAS) by leveraging linkage disequilibrium from a reference panel. We sought to (i) investigate the performance of imputation from the August 2010 release of the 1000 Genomes Project (1000GP) in an existing GWAS of prostate cancer, (ii) look for novel associations with prostate cancer risk, (iii) fine-map known prostate cancer susceptibility regions using an approximate Bayesian framework and stepwise regression, and (iv) compare power and efficiency of imputation and de novo sequencing.

METHODS

We used 2,782 aggressive prostate cancer cases and 4,458 controls from the NCI Breast and Prostate Cancer Cohort Consortium aggressive prostate cancer GWAS to infer 5.8 million well-imputed autosomal single nucleotide polymorphisms (SNPs).

RESULTS

Imputation quality, as measured by correlation between imputed and true allele counts, was higher among common variants than rare variants. We found no novel prostate cancer associations among a subset of 1.2 million well-imputed low-frequency variants. At a genome-wide sequencing cost of $2,500, imputation from SNP arrays is a more powerful strategy than sequencing for detecting disease associations of SNPs with minor allele frequencies (MAF) above 1%.

CONCLUSIONS

1000GP imputation provided dense coverage of previously identified prostate cancer susceptibility regions, highlighting its potential as an inexpensive first-pass approach to fine mapping in regions such as 5p15 and 8q24. Our study shows 1000GP imputation can accurately identify low-frequency variants and stresses the importance of large sample size when studying these variants. Prostate 73: 677–689, 2013. © 2012 Wiley Periodicals, Inc.

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