2 research outputs found
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
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Influence of Xenorhabdus Symbionts on Gonad Development and Pheromone Production of First-Generation Adult Steinernema Nematodes (Nematoda: Steinernematidae)
Entomopathogenic Steinernema nematodes (Nematoda: Steinernematidae) have a mutualistic relationship with Xenorhabdus bacteria (Gamma-Proteobacteria Enterobacteriaceae). The two partners form an insecticidal alliance that is successful in killing a wide range of insects. A few studies have shown that Steinernema IJs have an enhanced virulence and reproductive fitness when they associate with their cognate symbionts. However, there are unanswered questions regarding the physiological interactions that govern and perpetuate the interactions between different nematode developmental stages and their bacterial partners. In this study, we evaluated gonad development and maturation time of first-generation adults of S. carpocapsae and S. feltiae adults when reared under four bacterial scenarios: a) cognate symbiotic, b) non-cognate symbiotic bacterial strain, c) non-cognate symbiotic bacterial species and d) non-symbiotic bacteria (Serratia proteamaculans). For comparative purposes, we also considered adult nematodes reared in vivo in Galleria mellonella larvae to assess nematode development under natural conditions. Furthermore, in this study we also measured production of nematode pheromones (ascarosides), which play a key role in mating and reproduction. For this purpose, we considered in vitro rearing methods (with cognate and non-cognate Xenorhabdus symbionts) to qualitatively and quantitatively characterize ascarosides produced by first-generation adults. Our data showed that for both Steinernema spp. tested, time to adult maturation and gonad development was tightly dependent on the bacterial conditions under which juveniles were reared. However, contrasting results were observed when assessing total body length and gonad size. S. feltiae males and females size (body length and width) and respective gonad length were smaller when reared with a non-cognate symbiotic species. Additionally, non-symbiotic bacteria did not sustain S. feltiae maturation to adult stages. Contrarily, S. carpocapsae juveniles developed to adults when reared with any of the bacterial conditions tested, including with non-symbiotic Serratia proteamaculans. Additionally, S. carpocapsae adults, unlike S. feltiae, did not exhibit enhanced body and gonad size when reared with their cognate symbiont. In fact, S. carpocapsae males and females had larger gonad lengths when reared with a non-cognate symbiotic strain, XnAna (X. nematophila associated with S. anatoliense). S. carpocapsae males and females had significantly underdeveloped gonads when reared with non-symbiotic bacteria. In both Steinernema spp., sex ratio was not impacted by the bacterial condition. However, sex ratio (female:male) S. carpocapsae, decreased from 2:1 to 1:1 when reared with non-symbiotic bacteria. The body and gonad sizes of Steinernema spp. reared in vitro with their cognate symbiont were significantly smaller than those grown in vivo. Ascaroside production in either Steinernema spp. was not significantly impacted by the rearing conditions. In S. carpocapsae, a significant increase in glucoside-1 was observed when the nematodes were reared with cognate or non-cognate bacteria. No detectable quantities of asc-C11 were produced by S. feltiae nematodes when reared with a non-cognate symbiotic bacterial species. We conclude that bacterial symbionts influenced maturation and development of first-generation adults’ in both Steinernema spp. tested in this study. However, response to the bacterial symbionts was species specific. Additionally, this study showed that Xenorhabdus as a food source plays an important role in the type and amount of ascarosides produced by Steinernema spp.Release after 19-Dec-201