Dataset Information

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.

SUBMITTER: Mancuso N

PROVIDER: S-EPMC7534691 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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The contribution of rare variation to prostate cancer heritability.

Mancuso Nicholas N Rohland Nadin N Rand Kristin A KA Tandon Arti A Allen Alexander A Quinque Dominique D Mallick Swapan S Li Heng H Stram Alex A Sheng Xin X Kote-Jarai Zsofia Z Easton Douglas F DF Eeles Rosalind A RA Le Marchand Loic L Lubwama Alex A Stram Daniel D Watya Stephen S Conti David V DV Henderson Brian B Haiman Christopher A CA Pasaniuc Bogdan B Reich David D

Nature genetics 20151116 1

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 ...[more]

PMID: 26569126

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Project description:CONTEXT:Skeletal muscle mass (SMM) is one of the major components of human body composition, with deviations from normal values often leading to sarcopenia. OBJECTIVE:Our major aim was to conduct a genome-wide DNA methylation study in an attempt to identify potential genomic regions associated with SMM. DESIGN:This was a mixed cross-sectional and longitudinal study. SETTING:Community-based study. PARTICIPANTS:A total of 1550 middle-aged United Kingdom twins (monozygotic [MZ] and dizygotic [DZ]), 297 of which were repeatedly measured participated in the study. MAIN OUTCOME MEASURE:Appendicular lean mass assessed using dual-energy X-ray absorptiometry technology, and methylated DNA immunoprecipitation sequencing DNA methylation profiling genome-wide were obtained from each individual. RESULTS:Heritability estimate of SMM, with simultaneous adjustment for covariates obtained using variance decomposition analysis, was h(2) = 0.809 ± 0.050. After quality control and analysis of longitudinal stability, the DNA methylation data comprised of 723 029 genomic sites, with positive correlations between repeated measurements (Rrepeated = 0.114-0.905). Correlations between MZ and DZ twins were 0.51 and 0.38 at a genome-wide average, respectively, and clearly increased with Rrepeated. Testing for DNA methylation association with SMM in 50 discordant MZ twins revealed 36 081 nominally significant results, of which the top-ranked 134 signals (P < .01 and Rrepeated > 0.40) were subjected to replication in the sample of 1196 individuals. Seven SMM methylation association signals replicated at a false discovery rate less than 0.1, and these were located in or near genes DNAH12, CAND1, CYP4F29P, and ZFP64, which have previously been highlighted in muscle-related studies. Adjusting for age, smoking, and blood cell heterogeneity did not alter significance of these associations. CONCLUSION:This epigenome-wide study, testing longitudinally stable methylation sites, discovered and replicated a number of associations between DNA methylation at CpG loci and SMM. Four replicated signals were related to genes with potential muscle functions, suggesting that the methylome of whole blood may be informative of SMM variation.

Dataset Information

The contribution of rare variation to prostate cancer heritability.

Publications

The contribution of rare variation to prostate cancer heritability.

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