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The contribution of rare variation to prostate cancer heritability

Abstract

We report targeted sequencing of 63 known prostate cancer risk regions in a multi-ancestry study of 9,237 men and use the data to explore the contribution of low-frequency variation to disease risk. We show that SNPs with minor allele frequencies (MAFs) of 0.1–1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (42% of the variance contributed by SNPs with MAF of 0.1–50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78]) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits.

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Figure 1: Relationship between strength of selection, the coupling parameter τ and allelic effect sizes in prostate cancer using heritability partitioning for the African-ancestry sample.

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Acknowledgements

This work is supported in part by the US National Institutes of Health (R01 CA165862, U19 CA148537, UM1 CA164973, RC2 CA148085, U01 CA1326792, R21 CA182821 and U01 CA188392). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Many of the risk regions examined were discovered through contributions from: P. Hall (COGS), D.F.E., P. Pharoah, K. Michailidou, M.K. Bolla and Q. Wang (BCAC), A. Berchuck (OCAC), R.A.E., D.F.E., A.A. Al Olama, Z.K.-J. and S. Benlloch (PRACTICAL), G. Chenevix-Trench, A. Antoniou, L. McGuffog, F. Couch and K. Offit (CIMBA), J. Dennis, A.M. Dunning, A. Lee, E. Dicks, C. Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, J. Benitez, A. Gonzalez-Neira and the staff of the CNIO genotyping unit, J. Simard, D.V.C. Tessier, F. Bacot, D. Vincent, S. LaBoissière, F. Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, S.E. Bojesen, S.F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and J.M. Cunningham, S.A. Windebank, C.A. Hilker, J. Meyer and the staff of the Mayo Clinic Genotyping Core Facility. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112–GAME-ON initiative), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. D.R. is an Investigator of the Howard Hughes Medical Institute.

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Contributions

N.R., C.A.H. and D.R. defined the regions of interest. N.R., S.M. and D.R. designed the in-solution capture reagent. N.R., A.A. and D.Q. prepared libraries. N.R. performed capture and quality control sequencing. N.R., A.T. and S.M. performed sequence analyses. N.M. performed statistical analyses and simulations. K.A.R., A.T., H.L., A.S., X.S., Z.K.-J., D.F.E., R.A.E., the PRACTICAL consortium, L.L.M., A.L., D.S., S.W., D.V.C. and B.H. generated data and analysis tools. C.A.H., B.P. and D.R. supervised the work. All authors reviewed, revised and wrote feedback for the manuscript.

Corresponding authors

Correspondence to Christopher A Haiman, Bogdan Pasaniuc or David Reich.

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The authors declare no competing financial interests.

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A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–24, Supplementary Tables 2–36, 38 and 43–45, and Supplementary Note. (PDF 3934 kb)

Supplementary Dataset 1

Linkage-disequilibrium maps for the targeted loci (PDF 9178 kb)

Supplementary Table 1

Boundaries and capture information for the targeted loci. (XLSX 75 kb)

Supplementary Table 37

Association meta-analysis summary. (XLSX 48 kb)

Supplementary Table 39

Association analysis summary for the African-ancestry group. (XLSX 42 kb)

Supplementary Table 40

Association analysis summary for the European-ancestry group. (XLSX 40 kb)

Supplementary Table 41

Association analysis summary for the Japanese-ancestry group. (XLSX 42 kb)

Supplementary Table 42

Association analysis summary for the Latino-ancestry group. (XLSX 42 kb)

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Mancuso, N., Rohland, N., Rand, K. et al. The contribution of rare variation to prostate cancer heritability. Nat Genet 48, 30–35 (2016). https://doi.org/10.1038/ng.3446

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