Dataset Information

Replication of the 10q11 and Xp11 prostate cancer risk variants: results from a Utah pedigree-based study.

ABSTRACT: A recent genome-wide association study suggested seven new loci as associated with prostate cancer susceptibility. The strongest associated single nucleotide polymorphism (SNP) in each region was identified (rs2660753, rs9364554, rs6465657, rs10993994, rs7931342, rs2735839, rs5945619). We studied these seven SNPs in a replication study consisting of 169 familial prostate cancer cases selected from Utah high-risk prostate cancer pedigrees and 805 controls. We performed subset analyses for aggressive and early-onset prostate cancer. At a nominal significance level, two SNPs were found to be associated with prostate cancer: rs10993994 on chromosome 10q11 [odds ratio (OR), 1.42; 95% confidence interval (95% CI), 1.05-1.90; P = 0.022] and rs5945619 on chromosome Xp11 (OR, 1.54; 95% CI, 1.03-2.31; P = 0.035). Restricting analysis to familial prostate cancer cases with aggressive disease yielded very similar risk estimates at both SNPs. However, subset analysis for familial, early-onset disease indicated highly significant association evidence and substantially higher risk estimates for rs10993994 (OR, 2.20; 95% CI, 1.48-3.27; P < 0.0001). This result suggests that the higher risk estimates from the stage 1 cohort in the original study for rs10993994 may have been due to the early-onset and familial nature of the prostate cancer cases in that cohort. In conclusion, in a small case-control study of prostate cancer cases from Utah high-risk pedigrees, we have significantly replicated association of prostate cancer with rs10993994 (10q11) upon study-wide correction for multiple comparisons. We also nominally replicated the association of prostate cancer with rs5945619 (Xp11). In particular, it seems that the susceptibility locus at 10q11 maybe involved in familial, early-onset disease.

SUBMITTER: Camp NJ

PROVIDER: S-EPMC2697376 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Replication of the 10q11 and Xp11 prostate cancer risk variants: results from a Utah pedigree-based study.

Camp Nicola J NJ Farnham James M JM Wong Jathine J Christensen G Bryce GB Thomas Alun A Cannon-Albright Lisa A LA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20090331 4

A recent genome-wide association study suggested seven new loci as associated with prostate cancer susceptibility. The strongest associated single nucleotide polymorphism (SNP) in each region was identified (rs2660753, rs9364554, rs6465657, rs10993994, rs7931342, rs2735839, rs5945619). We studied these seven SNPs in a replication study consisting of 169 familial prostate cancer cases selected from Utah high-risk prostate cancer pedigrees and 805 controls. We performed subset analyses for aggress ...[more]

PMID: 19336566

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Project description:BackgroundWith the advent of next-generation sequencing (NGS) technologies, researchers are now generating a deluge of data on high dimensional genomic variations, whose analysis is likely to reveal rare variants involved in the complex etiology of disease. Standing in the way of such discoveries, however, is the fact that statistics for rare variants are currently designed for use with population-based data. In this paper, we introduce a pedigree-based statistic specifically designed to test for rare variants in family-based data. The additional power of pedigree-based statistics stems from the fact that while rare variants related to diseases or traits of interest occur only infrequently in populations, in families with multiple affected individuals, such variants are enriched. Note that while the proposed statistic can be applied with and without statistical weighting, our simulations show that its power increases when weighting (WSS and VT) are applied.ResultsOur working hypothesis was that, since rare variants are concentrated in families with multiple affected individuals, pedigree-based statistics should detect rare variants more powerfully than population-based statistics. To evaluate how well our new pedigree-based statistics perform in association studies, we develop a general framework for sequence-based association studies capable of handling data from pedigrees of various types and also from unrelated individuals. In short, we developed a procedure for transforming population-based statistics into tests for family-based associations. Furthermore, we modify two existing tests, the weighted sum-square test and the variable-threshold test, and apply both to our family-based collapsing methods. We demonstrate that the new family-based tests are more powerful than corresponding population-based test and they generate a reasonable type I error rate.To demonstrate feasibility, we apply the newly developed tests to a pedigree-based GWAS data set from the Framingham Heart Study (FHS). FHS-GWAS data contain approximately 5000 uncommon variants with frequencies less than 0.05. Potential association findings in these data demonstrate the feasibility of the software PB-STAR (note, PB-STAR is now freely available to the public).ConclusionOur tests show that when analyzing for rare variants, a pedigree-based design is more powerful than a population-based case-control design. We further demonstrate that a pedigree-based statistic's power to detect rare variants increases in direct relation to the proportion of affected individuals within the pedigree.

Dataset Information

Replication of the 10q11 and Xp11 prostate cancer risk variants: results from a Utah pedigree-based study.

Publications

Replication of the 10q11 and Xp11 prostate cancer risk variants: results from a Utah pedigree-based study.

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