Format

Send to

Choose Destination
Nat Genet. 2016 Jan;48(1):30-5. doi: 10.1038/ng.3446. Epub 2015 Nov 16.

The contribution of rare variation to prostate cancer heritability.

Author information

1
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
2
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
3
Broad Institute, Cambridge, Massachusetts, USA.
4
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
5
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
6
The Institute of Cancer Research, London, UK.
7
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
8
Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK.
9
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
10
School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
11
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

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.

PMID:
26569126
DOI:
10.1038/ng.3446
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center