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

Functional Roles of High-Affinity Glutamate Transporters in Cochlear Afferent Synaptic Transmission in the Mouse

In the cochlea, afferent transmission between inner hair cells and auditory neurons is mediated by glutamate receptors. Glutamate transporters located near the synapse and in spiral ganglion neurons are thought to maintain low synaptic levels of glutamate. We analyzed three glutamate transporter blockers for their ability to alter the effects of glutamate, exogenously applied to the synapse via perfusion of the scala tympani of the mouse, and compared that action to their ability to alter the effects of intense acoustic stimulation. Threo-beta-benzyloxyaspartate (TBOA) is a broad-spectrum glutamate transporter antagonist, affecting all three transporters [glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT1), and excitatory amino acid carrier 1 (EAAC1)]. l-serine-O-sulfate (SOS) blocks both GLAST and EAAC1 without effect on GLT1. Dihydrokainate (DHK) is selective for GLT1. Infusion of glutamate (10 μM for 220 min), TBOA (200 μM for 220 min), or SOS (100 μM for 180 min) alone did not alter auditory neural thresholds. When infused together with glutamate, TBOA and SOS produced significant neural threshold shifts, leaving otoacoustic emissions intact. In addition, both TBOA and SOS exacerbated noise-induced hearing loss by producing larger neural threshold shifts and delaying recovery. DHK did not alter glutamate- or noise-induced hearing loss. The evidence points to a major role for GLAST, both in protecting the synapse from exposure to excess extracellular glutamate and in attenuating hearing loss due to acoustic overstimulation

The Aging of the Middle Ear in 129S6/SvEvTac and CBA/CaJ Mice: Measurements of Umbo Velocity, Hearing Function, and the Incidence of Pathology

Measurements of umbo velocity and auditory brainstem response (ABR) were made on two different strains of mice, 129S6/SvEvTac (129S6) and CBA/CaJ (CB), within three different age ranges. The velocity measurements were made with a laser Doppler vibrometer using a semiclosed sound delivery system; the frequency range of accurate velocity measurements is from 1 to 21 kHz. The visual detection threshold of the ABR was determined at selected frequencies between 2 and 32 kHz. The velocity results suggest a small but significant change in umbo velocity with age in both strains, between the youngest (1.5–3 months) and mid-aged (12–14 months) groups. There is also a clear difference in the umbo velocity in the youngest animals of the two strains, with the 129S6 having more sensitive middle-ear function than the CB. These results support the existence of a small age-related loss in middle-ear sensitivity in the mouse that was first described in the BALB/6J strain. The age-related changes in middle-ear function observed in both CB and 129S6 are much smaller than the age-related decreases in ABR. Our results also describe a statistically significant increase in the incidence of middle-ear pathology with age in the 129S6

Trk agonist drugs rescue noise-induced hidden hearing loss

TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid–induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline, and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 hours after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the auditory brainstem response (ABR) were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact 1 year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of postexposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposures