Biology subjects

the PRACTICAL consortium

Publications and source records attributed to the PRACTICAL consortium.

2 recordsLinked to original sources

bioRxiv2018

Mendelian randomization does not support serum calcium in prostate cancer risk

Background: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies.\n\nObjective: We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer.\n\nDesign: A genetic instrument was constructed using 5 single nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (N [≤] 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls).\n\nResults: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI: 0.63-1.08; P=0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI: 0.57-1.70; P=0.93).\n\nConclusions: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.

epidemiology↗

bioRxiv2015

The contribution of rare variation to prostate cancer heritability

Although genome-wide association studies (GWAS) have found more than a hundred common susceptibility alleles for prostate cancer, the GWAS reported variants jointly explain only 33% of risk to siblings, leaving the majority of the familial risk unexplained. We use targeted sequencing of 63 known GWAS risk regions in 9,237 men from four ancestries (African, Latino, Japanese, and European) to explore the role of low-frequency variation in risk for prostate cancer. We find that the sequenced variants explain significantly more of the variance in the trait than the known GWAS variants, thus showing that part of the missing familial risk lies in poorly tagged causal variants at known risk regions. We report evidence for genetic heterogeneity in SNP effect sizes across different ancestries. We also partition heritability by minor allele frequency (MAF) spectrum using variance components methods, and find that a large fraction of heritability (0.12, s.e. 0.05; 95% CI [0.03, 0.21]) is explained by rare variants (MAF<0.01) in men of African ancestry. We use the heritability attributable to rare variants to estimate the coupling between selection and allelic effects at 0.48 (95% CI of [0.19, 0.78]) under the Eyre-Walker model. These results imply that natural selection has driven down the frequency of many prostate cancer risk alleles over evolutionary history. Overall our results show that a substantial fraction of the risk for prostate cancer in men of African ancestry lies in rare variants at known risk loci and suggests that rare variants make a significant contribution to heritability of common traits.

Genetics↗