7 research outputs found

    Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

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    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

    Adaptive Multiscale Methods for the Numerical Treatment of Systems of PDEs

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    These notes are concerned with numerical analysis issues arising in the solution of certain systems involving stationary and instationary linear variational problems. Standard examples are second order elliptic boundary value problems, where particular emphasis is placed on the treatment of essential boundary conditions, and linear parabolic equations. These operator equations serve as a core ingredient for control problems where in addition to the state, the solution of the PDE, a control is to be determined which together with the state minimizes a certain tracking-type objective functional. Having assured that the variational problems are well-posed, we discuss numerical schemes based on B-splines and B-spline-type wavelets as a particular multiresolution discretization methodology. The guiding principle is to devise fast and efficient solution schemes which are optimal in the number of arithmetic unknowns. We discuss optimal conditioning of the system matrices, numerical stability of discrete formulations, and adaptive approximations

    Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

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    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33)