Mancuso Nicholas, Rohland Nadin, Rand Kristin A, Tandon Arti, Allen Alexander, Quinque Dominique, Mallick Swapan, Li Heng, Stram Alex, Sheng Xin, Kote-Jarai Zsofia, Easton Douglas F, Eeles Rosalind A, Le Marchand Loic, Lubwama Alex, Stram Daniel, Watya Stephen, Conti David V, Henderson Brian, Haiman Christopher A, Pasaniuc Bogdan, Reich David
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.
Nat Genet. 2016 Jan;48(1):30-5. doi: 10.1038/ng.3446. Epub 2015 Nov 16.
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.
我们在一项对9237名男性的多血统研究中报告了对63个已知前列腺癌风险区域的靶向测序，并利用这些数据探讨低频变异对疾病风险的贡献。我们发现，次要等位基因频率（MAF）为0.1%-1%的单核苷酸多态性（SNP）解释了非洲血统男性中相当一部分前列腺癌风险。我们估计，这些SNP占风险方差的0.12（标准误（s.e.）=0.05）（约占MAF为0.1%-50%的SNP所贡献方差的42%）。这一贡献远大于该类SNP导致的中性变异比例，这意味着自然选择降低了许多前列腺癌风险等位基因的频率；根据艾尔-沃克模型，我们估计选择与等位基因效应之间的耦合系数为0.48（95%置信区间[0.19, 0.78]）。我们的结果表明，罕见变异对前列腺癌遗传风险的贡献不成比例，并提示罕见变异可能对其他常见性状也有巨大影响的可能性。
