title: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Nicholas
authors.identifier: http://orcid.org/0000-0002-9352-5927
authors.initials: N
authors.lastname: Mancuso
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Nadin
authors.initials: N
authors.lastname: Rohland
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Rand
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Arti
authors.initials: A
authors.lastname: Tandon
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Allen
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Quinque
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Swapan
authors.initials: S
authors.lastname: Mallick
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Heng
authors.identifier: http://orcid.org/0000-0003-4874-2874
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Stram
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Sheng
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: The Institute of Cancer Research, London, UK.|Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Eeles
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Alex
authors.initials: A
authors.lastname: Lubwama
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stram
authors.affiliation: School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Stephen
authors.initials: S
authors.lastname: Watya
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Henderson
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.|Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.|Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Reich
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D014454:Uganda