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Genome-wide two-locus epistasis scans in prostate cancer using two European populations

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Abstract

Approximately 40 single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk have been identified through genome-wide association studies (GWAS). However, these GWAS-identified PCa risk-associated SNPs can explain only a small proportion of heritability (~13%) of PCa risk. Gene–gene interaction is speculated to be one of the major factors contributing to the so-called missing heritability. To evaluate the gene–gene interaction and PCa risk, we performed a two-stage genome-wide gene–gene interaction scan using a novel statistical approach named “Boolean Operation-based Screening and Testing”. In the first stage, we exhaustively evaluated all pairs of SNP–SNP interactions for ~500,000 SNPs in 1,176 PCa cases and 1,101 control subjects from the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) study. No SNP–SNP interaction reached a genome-wide significant level of 4.4E−13. The second stage of the study involved evaluation of the top 1,325 pairs of SNP–SNP interactions (P interaction <1.0E−08) implicated in CGEMS in another GWAS population of 1,964 PCa cases from the Johns Hopkins Hospital (JHH) and 3,172 control subjects from the Illumina iControl database. Sixteen pairs of SNP–SNP interactions were significant in the JHH population at a P interaction cutoff of 0.01. However, none of the 16 pairs of SNP–SNP interactions were significant after adjusting for multiple tests. The current study represents one of the first attempts to explore the high-dimensional etiology of PCa on a genome-wide scale. Our results suggested a list of SNP–SNP interactions that can be followed in other replication studies.

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Acknowledgments

We thank all of the study subjects who participated in the JHH study and the urologists who provided their patients to the JHH study. We acknowledge the contribution of multiple physicians and researchers in designing and recruiting study subjects. We also acknowledge the National Cancer Institute Cancer Genetic Markers of Susceptibility Initiative (CGEMS) for making the data publicly available. We also want to thank Dr. Can Yang for kindly responding to all our questions related to BOOST software. This work was supported by a DOD grant to J.S (W81XWH-09-1-0488), an intramural funding from the Van Andel Research Institute to J.X, and a R01 grant from the National Cancer Institute (CA129684 J.X).

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Authors and Affiliations

  1. Center for Genetic Epidemiology and Prevention, Van Andel Research Institute, Grand Rapids, MI, USA

    Sha Tao, Timothy Webster & Jianfeng Xu

  2. Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Junjie Feng, Guangfu Jin, Fang-Chi Hsu, Seong-Tae Kim, Zhong Wang, Zheng Zhang, Siqun L. Zheng, Jianfeng Xu & Jielin Sun

  3. Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Junjie Feng, Guangfu Jin, Seong-Tae Kim, Zhong Wang, Zheng Zhang, Siqun L. Zheng, Jianfeng Xu & Jielin Sun

  4. Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Fang-Chi Hsu & Shyh-Huei Chen

  5. Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    William B. Isaacs

  6. Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Jianfeng Xu

Authors
  1. Sha Tao
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  2. Junjie Feng
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  3. Timothy Webster
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  4. Guangfu Jin
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  5. Fang-Chi Hsu
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  6. Shyh-Huei Chen
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  7. Seong-Tae Kim
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  8. Zhong Wang
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  9. Zheng Zhang
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  10. Siqun L. Zheng
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  11. William B. Isaacs
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  12. Jianfeng Xu
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  13. Jielin Sun
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Corresponding author

Correspondence to Jielin Sun.

Additional information

S. Tao and J. Feng contributed equally.

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Supplementary material 1 (DOCX 615 kb)

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Tao, S., Feng, J., Webster, T. et al. Genome-wide two-locus epistasis scans in prostate cancer using two European populations. Hum Genet 131, 1225–1234 (2012). https://doi.org/10.1007/s00439-012-1148-4

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  • DOI: https://doi.org/10.1007/s00439-012-1148-4

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