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

Pull-In and Snap-Through Analysis of Electrically Actuated Viscoelastic Curved Microbeam

Microbeams are key elements in most of the micro-electromechanical systems (MEMS). Electromechanical instability of microbeams in turn plays an important role in their applications. The shape and mechanical properties of microbeams dictate their functional characteristics. Focusing on their instability-based working mechanism, one can appreciate that viscoelasticity of MEMS materials cannot be neglected. Consequently, the analysis of instability in viscoelastic curved microbeams is an essential demand. In this research, assuming a clamped-clamped initially curved microbeam, the effects of viscoelastic behavior on the snap-through and pull-in instabilities are investigated. The standard inelastic linear solid model is used for the simulation of viscoelastic behavior. Integrodifferential governing equation of the curved viscoelastic microbeam is obtained by assuming modified couple stress theory and using Hamilton’s principle. By applying the Galerkin method, the obtained governing equation is discretized, converted to a nonlinear differential equation, and solved by MATLAB software. Through a quasi-static analysis, the voltage and location of snap-through and pull-in instabilities are identified. The effects of different viscoelastic parameters including the creep moduli and relaxation coefficient upon the snap-through and pull-in instabilities are investigated. The effects of different short- and long-term creeping characteristics of viscoelastic microbeam are studied and discussed in detail