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

Using the Cochlear Microphonic as a Tool to Evaluate Cochlear Function in Mouse Models of Hearing

The cochlear microphonic (CM) can be a useful analytical tool, but many investigators may not be fully familiar with its unique properties to interpret it accurately in mouse models of hearing. The purpose of this report is to develop a model for generation of the CM in wild-type (WT) and prestin knockout mice. Data and modeling results indicate that in the majority of cases, the CM is a passive response, and in the absence of outer hair cell (OHC) damage, mice lacking amplification are expected to generate WT levels of CM for inputs less than ~30 kHz. Hence, this cochlear potential is not a useful metric to estimate changes in amplifier gain. This modeling analysis may explain much of the paradoxical data in the literature. For example, various manipulations, including the application of salicylate and activation of the crossed olivocochlear bundle, reduce the compound action potential but increase or do not change the CM. Based on this current evaluation, CM measurements are consistent with early descriptions where this AC cochlear potential is dominated by basal OHCs, when recorded at the round window

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes