The contribution of rare variation to prostate cancer heritability.

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.

Nature genetics. 2015 Nov 16 [Epub ahead of print]

Nicholas Mancuso, Nadin Rohland, Kristin A Rand, Arti Tandon, Alexander Allen, Dominique Quinque, Swapan Mallick, Heng Li, Alex Stram, Xin Sheng, Zsofia Kote-Jarai, Douglas F Easton, Rosalind A Eeles, PRACTICAL consortium , Loic Le Marchand, Alex Lubwama, Daniel Stram, Stephen Watya, David V Conti, Brian Henderson, Christopher A Haiman, Bogdan Pasaniuc, David Reich

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , The Institute of Cancer Research, London, UK. , Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. , The Institute of Cancer Research, London, UK. , Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. , School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. , Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. , Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

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