Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Isolation and characterization of Pseudomonas syringae pv. porri from leek in Flanders

© 2015, Koninklijke Nederlandse Planteziektenkundige Vereniging. Pseudomonas syringae pv. porri causes bacterial leaf spot and blight of leek (Allium porrum) and is in wet crop seasons responsible for substantial losses. The local diversity within this pathogen in Flanders, Belgium, was investigated to obtain insights into its epidemiology. Therefore, symptomatic leek leaves were collected from 112 fields and bacteria were isolated. An oxidase negative, HR positive, fluorescent Pseudomonas was consistently recovered from the diseased tissues. Isolates were identified as P. syringae pv. porri by rpoD gene sequencing and by confirmation of pathogenicity in leek. Genomic profiles generated with BOX-PCR subdivided them into two groups, with one group containing 5 of the 37 analyzed strains. Those five isolates were all obtained in 2012 and the plant origins indicated seed transmitted infection. Draft genome sequences were produced for a P. syringae pv. porri strain from each BOX group and sequences of seven housekeeping genes were extracted for multi locus sequence analysis (MLSA). This resulted in the clustering of both P. syringae pv. porri strains with the P. syringae pv. oryzae strain 1_6 as did the whole genome sequence comparisons by ANI analysis. The P. syringae pv. porri isolates, designated LMG 28495 and LMG 28496, differed in a type III effector gene, HrpW, and in the number of mobile elements in the genome. Overall, the data demonstrate that two P. syringae pv. porri variants are present in symptomatic leek in Flanders which can be discriminated and possibly traced using a genomic profiling method such as BOX-PCR. Furthermore, the draft genome sequences of both strains will facilitate the development of sensitive and specific methods for early detection.status: publishe

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling