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

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

A Riemannian Geometry Theory of Three-Dimensional Binocular Visual Perception

We present a Riemannian geometry theory to examine the systematically warped geometry of perceived visual space attributable to the size⁻distance relationship of retinal images associated with the optics of the human eye. Starting with the notion of a vector field of retinal image features over cortical hypercolumns endowed with a metric compatible with that size⁻distance relationship, we use Riemannian geometry to construct a place-encoded theory of spatial representation within the human visual system. The theory draws on the concepts of geodesic spray fields, covariant derivatives, geodesics, Christoffel symbols, curvature tensors, vector bundles and fibre bundles to produce a neurally-feasible geometric theory of visuospatial memory. The characteristics of perceived 3D visual space are examined by means of a series of simulations around the egocentre. Perceptions of size and shape are elucidated by the geometry as are the removal of occlusions and the generation of 3D images of objects. Predictions of the theory are compared with experimental observations in the literature. We hold that the variety of reported geometries is accounted for by cognitive perturbations of the invariant physically-determined geometry derived here. When combined with previous description of the Riemannian geometry of human movement this work promises to account for the non-linear dynamical invertible visual-proprioceptive maps and selection of task-compatible movement synergies required for the planning and execution of visuomotor tasks

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

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)