Biology subjects

Zheng, W.

Publications and source records attributed to Zheng, W..

At least 235 records · Page 13Linked to original sources

bioRxiv2019

Fungal traits important for soil aggregation

Soil health and sustainability is essential for ecosystem functioning and human well-being. Soil structure, the complex arrangement of soil into aggregates and pore spaces, is a key feature of soils under the influence of soil life. Soil biota, and among them filamentous saprobic fungi, have well-documented effects on soil aggregation. However, it is unclear what fungal properties, or traits, contribute to the overall positive effect on soil aggregation. So far, we lack a systematic investigation of a broad suite of fungal species for their trait expression and the relation of these traits to their soil aggregation capability.\n\nHere, we apply a trait-based approach to a set of 15 traits measured under standardized conditions on 31 fungal strains including Ascomycota, Basidiomycota and Mucoromycota, all isolated from the same soil.\n\nWe found a spectrum of soil aggregate formation capability ranging from neutral to positive and large differences in trait expression among strains. We identified biomass density (positive effects), leucine aminopeptidase activity (negative effects) and phylogeny as important modulators of fungal aggregate formation capability. Our results point to a typical suite of traits characterizing fungi that are good soil aggregators; this could inform screening for fungi to be used in biotechnological applications, and illustrates the power of employing a trait-based approach to unravel biological mechanisms of soil aggregation, which could now be extended to other organism groups.

ecology↗

bioRxiv2019

Carbon dots for efficient siRNA delivery and gene silencing in plants

The Initiation of RNA interference (RNAi) by topically applied double stranded RNA (dsRNA) has potential applications for plant functional genomics, crop improvement and crop protection. The primary obstacle for the development of this technology is efficient delivery of RNAi effectors. The plant cell wall is a particularly challenging barrier to the delivery of macromolecules. Many of the transfection agents that are commonly used with animal cells produce nanocomplexes that are significantly larger than the size exclusion limit of the plant cell wall. Utilizing a class of very small nanoparticles called carbon dots, a method of delivering siRNA into the model plant Nicotiana benthamiana and tomato is described. Low-pressure spray application of these formulations with a spreading surfactant resulted in strong silencing of GFP transgenes in both species. The delivery efficacy of carbon dot formulations was also demonstrated by silencing endogenous genes that encode two sub-units of magnesium chelatase, an enzyme necessary for chlorophyll synthesis. The strong visible phenotypes observed with the carbon dot facilitated delivery were validated by measuring significant reductions in the target gene transcript and/or protein levels. Methods for the delivery of RNAi effectors into plants, such as the carbon dot formulations described here, could become valuable tools for gene silencing in plants with practical applications in plant functional genomics and agriculture.

plant biology↗

bioRxiv2019

Multiple Binding Configurations of Fis Protein Pairs on DNA: Facilitated Dissociation versus Cooperative Dissociation

As a master transcription regulator, Fis protein influences over two hundred genes of E-coli. Fis proteins non-specific binding to DNA is widely acknowledged, and its kinetics of dissociation from DNA is strongly influenced by its surroundings: the dissociation rate increases as the concentration of Fis protein in the solution-phase increases. In this study, we use computational methods to explore the global binding energy landscape of the Fis1:Fis2:DNA ternary complex. The complex contains a binary-Fis molecular dyad whose formation relies on complex structural rearrangements. The simulations allow us to distinguish several different pathways for the dissociation of the protein from DNA with different functional outcomes, and involving different protein stoichiometries: 1. Simple exchange of proteins and 2. Cooperative unbinding of two Fis proteins to yield bare DNA. In the case of exchange, the protein on the DNA is replaced by solution-phase protein through competition for DNA binding sites. This process seen in fluorescence imaging experiments has been called facilitated dissociation. In the latter case of cooperative unbinding of pairs, two neighboring Fis proteins on DNA form a unique binary-Fis configuration via protein-protein interactions, which in turn leads to the co-dissociation of both molecules simultaneously, a process akin to the \"molecular stripping\" seen in the NF{kappa}B/I{kappa}B genetic broadcasting system. This simulation shows that the existence of multiple binding configurations of transcription factors can have a significant impact on the kinetics and outcome of transcription factor dissociation from DNA, with important implications for the systems biology of gene regulation by Fis.

biophysics↗

bioRxiv2019

Extra-cellular matrix induced by steroids through a G-protein coupled receptor in a Drosophila model of renal fibrosis

Aldosterone is produced by the mammalian adrenal cortex to modulate blood pressure and fluid balance, however excessive, prolonged aldosterone production promotes fibrosis and kidney failure. How aldosterone triggers disease may involve actions that are independent of its canonical mineralocorticoid receptor. Here we present a Drosophila model of renal pathology caused by excess extra-cellular matrix formation, stimulated by exogenous aldosterone and insect ecdysone steroids. Chronic administration of aldosterone or ecdysone induces expression and accumulation of collagen-like pericardin at adult nephrocytes - podocyte-like cells that filter circulating hemolymph. Excess pericardin deposition disrupts nephrocyte (glomerular) filtration and causes proteinuria in Drosophila, hallmarks of mammalian kidney failure. Steroid-induced pericardin arises from cardiomyocytes associated with nephrocytes, reflecting an analogous role of mammalian myofibroblasts in fibrotic disease. Remarkably, the canonical ecdysteroid nuclear hormone receptor, ecdysone receptor EcR, is not required for aldosterone or ecdysone to stimulate pericardin production or associated renal pathology. Instead, these hormones require a cardiomyocyte-associated G-protein coupled receptor, dopamine-EcR (dopEcR), a membrane-associated receptor previously characterized in the fly brain as affecting behavior. This Drosophila renal disease model reveals a novel signaling pathway through which steroids may potentially modulate human fibrosis through proposed orthologs of dopEcR.\n\nSignificance StatementAldosterone regulates salt and fluid homeostasis, yet excess aldosterone contributes to renal fibrosis. Aldosterone acts through a nuclear hormone receptor, but an elusive, G-protein coupled receptor (GPCR) is thought to also mediate the hormones pathology. Here we introduce a Drosophila model of renal fibrosis. Flies treated with human aldosterone produce excess extra-cellular matrix and that causes kidney pathology. Flies treated with the insect steroid ecdysone produce similar pathology, and from this analogous response we identify an alternative receptor through which steroids mediate renal fibrosis -- the GPCR dopamine-Ecdysone Receptor (dopEcR). dopEcR functions in heart muscle cells associated with nephrocytes, analogous to the role of myofibroblasts in human fibrosis. This finding opens avenues to identify mammalian GPCR homologs of dopEcR through which aldosterone mediates renal fibrosis.

pathology↗

bioRxiv2019

Alterations of the pulmonary immunity are independent of spontaneous pneumonia in an experimental model of ischemic stroke

Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multi-factorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies of focal ischemic stroke induction, using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that severe brain damage results in massive apoptosis and functional defects of lymphocytes in the spleen, thymus, and peripheral blood. However, how immune alternations in remote tissues lead to a greater susceptibility to lung infections is not well-understood. Importantly, how ischemic stroke alters immune-cell fates, and the expression of cytokines and chemokines in the lungs that directly impact pulmonary immunity, has not been characterized. We report here that ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells (DCs), but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, and eosinophils in the lungs. The depletion of immune cells in the lungs is not caused by apoptosis, cell infiltration to the brain, or spontaneous pneumonia following ischemic stroke as previously described, but correlates with a significant reduction in the levels of multiple chemokines in the lungs, including: CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. These findings suggest that ischemic stroke negatively impacts pulmonary immunity to become more susceptible for SAP development. Further investigation into the mechanisms that control pulmonary immune alternations following ischemic stroke may identify novel diagnostic or therapeutic targets for SAP.

immunology↗

bioRxiv2019

Volumetric two-photon imaging in live cells and embryos via axially gradient excitation

Two-photon microscopy(TPM) that features subcellular resolution, intrinsic optical sectioning ability, and deep penetration in sample is a powerful tool of bioimaging. However, the process of layer-by-layer scanning to form a 3D image inherently limits the volumetric imaging speed and significantly increases the phototoxicity. Here we develop a gradient TPM technique that enables rapid volumetric imaging by only acquiring two 2D images. By sequentially exciting the specimen with two axially elongated two-photon beams with complementary gradient intensities, the axial positions of fluorophores can be decoded from the intensity ratio of the paired images. We achieve an axial localization accuracy of 0.728 {+/-} 0.657 m, which is sufficient for rapid 3D subcellular imaging. We demonstrate the flexibility of the gradient TPM on a variety of sparsely labelled samples, including bead phantoms, mouse brain tissues, live macrophages and live nematode embryos. The results show that, compared with conventional TPM, the 3D imaging speed increases 6 folds while the photobleaching and photodamage are extremely reduced.

bioengineering↗

bioRxiv2019

A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73-associated reduction of invasiveness act via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 and CARM1 knockout alter the epigenetic plasticity with remarkable difference, arguing distinct modes of action between the small-molecule and genetic perturbation. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

biochemistry↗

bioRxiv2019

Cryo-EM Map of the CFA/I Pilus Rod

Enterotoxigenic Escherichia coli (ETEC) are common agents of diarrhea for travelers and a major cause of mortality in children in developing countries. To attach to intestinal cells ETEC express colonization factors, among them CFA/I, which are the most prevalent factors and are the archetypical representative of Class 5 pili. Due to their helical quaternary structure that can be unwound and works as a damper of force, CFA/I pili help ETEC bacteria withstand intestinal fluid motion. We report in this work the CFA/I pilus structure at 4.0 [A] resolution and report details of the donor strand complementation. The density map allows us to identify the buried surface area between subunits, and these regions are correlated to quaternary structural stability in class 5 and Chaperone-Usher pili. In addition, from the EM map we also predicted that residue 13 (proline) of the N-terminal {beta}-strand could have a major impact on the filaments structural stability. Therefore, we used optical tweezers to measure and compare the stability of the quaternary structure of wild type CFA/I and point-mutated CFA/I in which proline 13 was changed to a non-polar residue, phenylalanine. We found that pili with this mutated CFA/I require a lower force to unwind, supporting our hypothesis that Pro 13 is important for structural stability. The high-resolution CFA/I pilus structure presented in this work and the analysis of structural stability will be useful for the development of novel antimicrobial drugs that target the pilus structure to reduce its damping properties, which are needed for initial attachment and sustained adhesion of ETEC.\n\nSynopsisThe structure of a common virulence factor expressed on the surface of diarrheacausing bacteria, CFA/I pili, has been determined at 4.0 [A] resolution. The role of proline 13 in stabilizing the pilus structure has been confirmed using force-measuring optical tweezers on wild type and point-mutated pili.

molecular biology↗

bioRxiv2019

The AAA+ ATPase TorsinA polymerizes into hollow tubes with a helical periodicity of 8.5 subunits per turn

TorsinA is an ER-resident AAA+ ATPase, whose single residue deletion of glutamate E303 results in the genetic neuromuscular disease primary dystonia. TorsinA is a highly unusual AAA+ ATPase in that it needs an external activator. Also, it appears not to thread a peptide substrate through a narrow central channel, in contrast to its closest structural homologs. Here, we examined the oligomerization of TorsinA to get closer to a molecular understanding of the still enigmatic function of it. We observe TorsinA to form helical filaments, which we analyzed by cryo-electron microscopy using helical reconstruction. The 4.4 [A] structure reveals long hollow tubes with a helical periodicity of 8.5 subunits per turn, and an inner cavity of [~]4 nm diameter. We further show that the protein is able to induce tubulation of membranes in vitro, an observation that may reflect an entirely new characteristic of AAA+ ATPases. We discuss the implications of these observations for TorsinA function.

biochemistry↗

bioRxiv2019

Unmatched level of molecular convergence among deeply divergent complex multicellular fungi

Convergent evolution is pervasive in nature, but it is poorly understood how various constraints and natural selection limit the diversity of evolvable phenotypes. Here, we report that, despite >650 million years of divergence, the same genes have repeatedly been co-opted for the development of complex multicellularity in the two largest clades of fungi--the Ascomycota and Basidiomycota. Co-opted genes have undergone duplications in both clades, resulting in >81% convergence across shared multicellularity-related families. This convergence is coupled with a rich repertoire of multicellularity-related genes in ancestors that predate complex multicellular fungi, suggesting that the coding capacity of early fungal genomes was well suited for the repeated evolution of complex multicellularity. Our work suggests that evolution may be predictable not only when organisms are closely related or are under similar selection pressures, but also if the genome biases the potential evolutionary trajectories organisms can take, even across large phylogenetic distances.

evolutionary biology↗

bioRxiv2018

Evaluating causal associations between previously reported risk factors and epithelial ovarian cancer: a Mendelian randomization analysis

BackgroundPreviously reported observational associations between risk factors and epithelial ovarian cancer (EOC) could reflect residual confounding, reverse causation, or measurement error. Mendelian randomization (MR) uses genetic variants as proxies for modifiable risk factors to strengthen causal inference in observational studies.\n\nMethodsWe used MR to evaluate the causal role of 13 previously reported risk factors in overall and histotype-specific EOC in up to 25,509 case subjects and 40,941 controls in the Ovarian Cancer Association Consortium. Inverse-variance weighted models were employed to generate effect estimates and MR-Egger, weighted median, and weighted mode were performed to examine evidence of horizontal pleiotropy. A Bonferroni-corrected P-value threshold was used to establish \"strong evidence\" (P<0.0038) and \"suggestive evidence\" (0.0038<P<0.05) for associations.\n\nResultsThere was strong or suggestive evidence that 9 of 13 risk factors were causally associated with overall or histotype-specific EOC. Genetic liability to endometriosis was strongly associated with EOC (OR per log odds higher liability: 1.27,95%CI:1.16-1.40;P=6.94x10-7) and lifetime smoking exposure was suggestively associated with EOC (OR per unit increase in smoking score:1.36,95%CI:1.04-1.78;P=0.02). In histotype-stratified analyses, the strongest associations found were between: height and clear cell carcinoma (OR per SD increase:1.36,95%CI:1.15-1.61;P=0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset:1.09,95% CI:1.02-1.16;P=0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per log odds higher liability:0.74,95% CI:0.62-0.90;P=0.002). There was little evidence that genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone-binding globulin were associated with ovarian cancer or its subtypes.\n\nConclusionsOur comprehensive examination of possible etiological drivers of ovarian carcinogenesis supports a causal role for few of these factors in epithelial ovarian cancer and suggests distinct etiologies across histotypes.

epidemiology↗

bioRxiv2018

The association between low-density lipoprotein cholesterol predicted by HMGCR genetic variants and breast cancer risk may be mediated by body mass index

Orho-Melander et al. recently reported that lower low-density lipoprotein cholesterol (LDLC) as predicted by the T-allele of the variant rs12916 in HMGCR is associated with a decreased risk of developing breast cancer [odds ratio (OR) = 0.89; 95% confidence interval (CI): 0.82-0.96].1 This analysis was embedded in a wider Mendelian randomization (MR) study performed using genotype data from a prospective cohort of 26,589 individuals that included 16,022 women and 1176 incident breast cancer cases. HMGCR encodes 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme inhibited by statins. The T-allele of rs12916 is associated with reduced HMGCR expression and therefore, in principle, its effects should be analogous to the effects of lifelong statin administration starting at birth.2 The MR study of Orho-Melander et al. also found that a genome-wide LDLC score based on 32 independent LDLC-associated single nucleotide polymorphisms (SNPs) was not associated with breast cancer. In light of this finding, they suggest that the protective effect of the rs12916 T-allele on breast cancer may either be specific to LDLC lowering via genetic inhibition of HMGCR or be the result of a distinct mechanism that is regulated by rs12916 and HMGCR.

epidemiology↗

bioRxiv2018

Sleep and Motor Control by a Basal Ganglia Circuit

From invertebrates to humans, a defining feature of sleep is behavioral immobility(Campbell and Tobler, 1984; Hendricks et al., 2000; Shaw et al., 2000). In mammals, diminished electromyographic (EMG) activity is a major criterion for both rapid eye movement (REM) and non-REM (NREM) sleep. However, the relationship between sleep and motor control at the neuronal level remains poorly understood. Here we show that regions of the basal ganglia long known to be essential for motor suppression also play a key role in sleep generation. Optogenetic or chemogenetic activation of GABAergic neurons in mouse substantia nigra pars reticulata (SNr) strongly increased both REM and NREM sleep, whereas their inactivation suppressed sleep and increased wakefulness. Analysis of natural home-cage behavior showed that mice transition sequentially through several behavioral states: locomotion, non-locomotor movement, quiet wakefulness, and sleep. Activation/inactivation of SNr neurons promoted/suppressed sleep by biasing the direction of progression through the natural behavioral sequence. Virus-mediated circuit tracing showed that SNr GABAergic neurons project to multiple wake-promoting monoaminergic cell groups in addition to the thalamus and mesencephalic locomotor region, and activating each projection promoted sleep. Within the thalamus, direct optogenetic inactivation of glutamatergic neurons is sufficient to enhance sleep, but the effect is largely restricted to the regions receiving SNr projection. Furthermore, a major source of excitatory inputs to the SNr is the subthalamic nucleus (STN), and activation of neurotensin-expressing glutamatergic neurons in the STN also promoted sleep. Together, these results demonstrate a key role of the STN-SNr basal ganglia pathway in sleep generation and reveal a novel circuit mechanism linking sleep and motor control.

neuroscience↗

bioRxiv2018

Single-cell RNA-seq reveals distinct dynamic behavior of sex chromosomes during early human embryogenesis

AbstractO_ST_ABSBackgroundC_ST_ABSSeveral animal and human studies have demonstrated that sex affects kinetics and metabolism during early embryo development. However, the mechanism governing these differences at the molecular level is unknown, warranting a systematic profiling of gene expression in males and females during embryogenesis.\n\nFindingsWe performed comprehensive analyses of gene expression comparing male and female embryos using available single-cell RNA-sequencing data of 1607 individual cells from 99 human preimplantation embryos, covering development stages from 4-cell to late blastocyst (E2 to E7). Consistent chromosome-wide transcription of autosomes was observed, while sex chromosomes showed significant differences after embryonic genome activation (EGA). Differentially expressed genes (DE genes) in male and female embryos mainly involved in the cell cycle, protein translation and metabolism. The Y chromosome was initially activated by pioneer genes, RPS4Y1 and DDX3Y, while the two X chromosomes in female were widely activated after EGA. Expression of X-linked genes in female significantly declined at the late blastocyst stage, especially in trophectoderm cells, revealing a rapid process of dosage compensation.\n\nConclusionsWe observed imbalanced expression from sex chromosomes in male and female embryos during EGA, with dosage compensation occurring first in female trophectoderm cells. Studying the effect of sex differences during human embryogenesis, as well as understanding the mechanism of X chromosome inactivation and its correlation with early miscarriage, will provide a basis for advancing assisted reproductive technology (ART) and thereby improve the treatment of infertility and possibly enhance reproductive health.

developmental biology↗

bioRxiv2018

How to build a mycelium: tradeoffs in fungal architectural traits

The fungal mycelium represents the essence of the fungal lifestyle, and understanding how a mycelium is constructed is of fundamental importance in fungal biology and ecology. Previous studies have examined initial developmental patterns or focused on a few strains, often mutants of model species, and frequently grown under non-harmonized growth conditions; these factors currently collectively hamper systematic insights into rules of mycelium architecture. To address this, we here use a broader suite of fungi (31 species including members of the Ascomycota, Basidiomycota and Mucoromycotina), all isolated from the same soil, and test for ten architectural traits under standardized laboratory conditions.\n\nWe find great variability in traits among the saprobic fungal species, and detect several clear tradeoffs in mycelial architecture, for example between internodal length and hyphal diameter. Within the constraints so identified, we document otherwise great versatility in mycelium architecture in this set of fungi, and there was no evidence of trait syndromes as might be expected.\n\nOur results point to an important dimension of fungal properties with likely consequences for coexistence within local communities, as well as for functional complementarity (e.g. decomposition, soil aggregation).

ecology↗

bioRxiv2018

Growth rate trades off with enzymatic investment in soil filamentous fungi

Saprobic soil fungi drive many important ecosystem processes, including decomposition, and many of their effects are related to growth rate and enzymatic ability. In mycology, there has long been the implicit assumption of trade-off between growth and enzymatic investment, which we here test. Using a set of 31 filamentous fungi isolated from the same ecosystem, we measured growth rate (as colony radial extension) and enzymatic repertoire (activities of four enzymes: laccase, cellobiohydrolase, leucine aminopeptidase and acid phosphatase). Our results support the existence of a trade-off, however only for the enzymes representing a larger metabolic cost (laccase and cellobiohydrolase). Our study offers new insights into functional complementarity within the soil fungal community in a number of ecosystem processes, and experimentally supports an enzymatic investment/ growth rate tradeoff in explaining phenomena including substrate succession.

ecology↗

bioRxiv2018

Genome analysis of the unicellular eukaryote Euplotes vannus provides insights into mating type determination and tolerance to environmental stresses

As a model organism in studies of cell and environmental biology, the free-living and cosmopolitan ciliated protist Euplotes vannus has more than ten mating types (sexes) and shows strong resistance to environmental stresses. However, the molecular basis of its sex determination mechanism and how the cell responds to stress remain largely unknown. Here we report a combined analysis of de novo assembled high-quality macronucleus (MAC; i.e. somatic) genome and partial micronucleus (MIC; i.e. germline) genome of Euplotes vannus. Furthermore, MAC genomic and transcriptomic data from several mating types of E. vannus were investigated and gene expression levels were profiled under different environmental stresses, including nutrient scarcity, extreme temperature, salinity and the presence of free ammonia. We found that E. vannus, which possesses gene-sized nanochromosomes in its MAC, shares a similar pattern on frameshifting and stop codon usage as Euplotes octocarinatus and may be undergoing incipient sympatric speciation with Euplotes crassus. Somatic pheromone loci of E. vannus are generated from programmed DNA rearrangements of multiple germline macronuclear destined sequences (MDS) and the mating types of E. vannus are distinguished by the different combinations of pheromone loci instead of possessing mating type-specific genes. Lastly, we linked the resilience to environmental temperature change to the evolved loss of temperature stress-sensitive regulatory regions of HSP70 gene in E. vannus. Together, the genome resources generated in this study, which are available online at Euplotes vannus DB (http://evan.ciliate.org), provide new evidence for sex determination mechanism in eukaryotes and common pheromone-mediated cell-cell signaling and cross-mating.

genomics↗

bioRxiv2018

Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here, we integrate the largest PrCa GWAS (N=142,392) with gene expression measured in 45 tissues (N=4,458), including normal and tumor prostate, to perform a multi-tissue transcriptomewide association study (TWAS) for PrCa. We identify 235 genes at 87 independent 1Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2Mb. 24 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at pre-defined level; this reduced the list of 235 associations to 120 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

genetics↗