Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Network science: Ising states of matter.

Network science provides very powerful tools for extracting information from interacting data. Although recently the unsupervised detection of phases of matter using machine learning has raised significant interest, the full prediction power of network science has not yet been systematically explored in this context. Here we fill this gap by providing an in-depth statistical, combinatorial, geometrical, and topological characterization of 2D Ising snapshot networks (IsingNets) extracted from Monte Carlo simulations of the 2D Ising model at different temperatures, going across the phase transition. Our analysis reveals the complex organization properties of IsingNets in both the ferromagnetic and paramagnetic phases and demonstrates the significant deviations of the IsingNets with respect to randomized null models. In particular percolation properties of the IsingNets reflect the existence of the symmetry between configurations with opposite magnetization below the critical temperature and the very compact nature of the two emerging giant clusters revealed by our persistent homology analysis of the IsingNets. Moreover, the IsingNets display a very broad degree distribution and significant degree-degree correlations and weight-degree correlations demonstrating that they encode relevant information present in the configuration space of the 2D Ising model. The geometrical organization of the critical IsingNets is reflected in their spectral properties deviating from the one of the null model. This work reveals the important insights that network science can bring to the characterization of phases of matter. The set of tools described hereby can be applied as well to numerical and experimental data.

Right-sided Morgagni diaphragmatic hernia presenting as isolated left shoulder pain.

A woman in her 60s presented to the emergency department with excruciating, deep left shoulder pain and was found to have a right-sided Morgagni hernia, a rare type of congenital diaphragmatic hernia (CDH). She did not have chest pain, palpitations, shortness of breath, cough, abdominal pain, constipation, diarrhoea, nausea, vomiting or other symptoms classically associated with CDHs in adults. Laparoscopic robotic-assisted repair with mesh placement was performed, and the patient's recovery was uncomplicated, with no recurrence of shoulder pain. Our patient's presentation was unusual due to the absence of symptoms typically seen with CDHs in adults, and the presence of contralateral, left-sided shoulder pain with a right-sided Morgagni hernia.

Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Accelerating Genome- and Phenome-Wide Association Studies using GPUs - A case study using data from the Million Veteran Program.

The expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.

Integrated organismal responses induced by projected levels of CO2 and temperature exposures in the early life stages of lake sturgeon.

Atmospheric CO2 and temperature are rising concurrently, and may have profound impacts on the transcriptional, physiological and behavioural responses of aquatic organisms. Further, spring snowmelt may cause transient increases of pCO2 in many freshwater systems. We examined the behavioural, physiological and transcriptomic responses of an ancient fish, the lake sturgeon (Acipenser fulvescens) to projected levels of warming and pCO2 during its most vulnerable period of life, the first year. Specifically, larval fish were raised in either low (16°C) or high (22°C) temperature, and/or low (1000 µatm) or high (2500 µatm) pCO2 in a crossed experimental design over approximately 8 months. Following overwintering, lake sturgeon were exposed to a transient increase in pCO2 of 10,000 µatm, simulating a spring melt based on data in freshwater systems. Transcriptional analyses revealed potential connections to otolith formation and reduced growth in fish exposed to high pCO2 and temperature in combination. Network analyses of differential gene expression revealed different biological processes among the different treatments on the edges of transcriptional networks. Na+/K+-ATPase activity increased in fish not exposed to elevated pCO2 during development, and mRNA abundance of the ß subunit was most strongly predictive of enzyme activity. Behavioural assays revealed a decrease in total activity following an acute CO2 exposure. These results demonstrate compensatory and compounding mechanisms of pCO2 and warming dependent on developmental conditions in lake sturgeon. Conserved elements of the cellular stress response across all organisms provide key information for how other freshwater organisms may respond to future climate change.

Topological Kolmogorov complexity and the Berezinskii-Kosterlitz-Thouless mechanism.

Topology plays a fundamental role in our understanding of many-body physics, from vortices and solitons in classical field theory to phases and excitations in quantum matter. Topological phenomena are intimately connected to the distribution of information content that, differently from ordinary matter, is now governed by nonlocal degrees of freedom. However, a precise characterization of how topological effects govern the complexity of a many-body state, i.e., its partition function, is presently unclear. In this paper, we show how topology and complexity are directly intertwined concepts in the context of classical statistical mechanics. We concretely present a theory that shows how the Kolmogorov complexity of a classical partition function sampling carries unique, distinctive features depending on the presence of topological excitations in the system. We confront two-dimensional Ising, Heisenberg, and XY models on several topologies and study the corresponding samplings as high-dimensional manifolds in configuration space, quantifying their complexity via the intrinsic dimension. While for the Ising and Heisenberg models the intrinsic dimension is independent of the real-space topology, for the XY model it depends crucially on temperature: across the Berezkinskii-Kosterlitz-Thouless (BKT) transition, complexity becomes topology dependent. In the BKT phase, it displays a characteristic dependence on the homology of the real-space manifold, and, for g-torii, it follows a scaling that is solely genus dependent. We argue that this behavior is intimately connected to the emergence of an order parameter in data space, the conditional connectivity, which displays scaling behavior. Our approach paves the way for an understanding of topological phenomena emergent from many-body interactions from the perspective of Kolmogorov complexity.

Beyond Local Structures in Critical Supercooled Water through Unsupervised Learning.

The presence of a second critical point in water has been a topic of intense investigation for the last few decades. The molecular origins underlying this phenomenon are typically rationalized in terms of the competition between local high-density (HD) and low-density (LD) structures. Their identification often requires designing parameters that are subject to human intervention. Herein, we use unsupervised learning to discover structures in atomistic simulations of water close to the liquid-liquid critical point (LLCP). Encoding the information on the environment using local descriptors, we do not find evidence for two distinct thermodynamic structures. In contrast, when we deploy nonlocal descriptors that probe instead heterogeneities on the nanometer length scale, this leads to the emergence of LD and HD domains rationalizing the microscopic origins of the density fluctuations close to criticality.

The role of the antennal glands and gills in acid-base regulation and ammonia excretion of a marine osmoconforming brachyuran.

The excretory mechanisms of stenohaline marine osmoconforming crabs are often compared to those of the more extensively characterized euryhaline osmoregulating crabs. These comparisons may have limitations, given that unlike euryhaline brachyurans the gills of stenohaline marine osmoconformers possess ion-leaky paracellular pathways and lack the capacity to undergo ultrastructural changes that can promote ion-transport processes in dilute media. Furthermore, the antennal glands of stenohaline marine osmoconformers are poorly characterized making it difficult to determine what role urinary processes play in excretion. In the presented study, ammonia excretory processes as well as related acid-base equivalent transport rates and mechanisms were investigated in the Dungeness crab, Metacarcinus magister - an economically valuable stenohaline marine osmoconforming crab. Isolated and perfused gills were found to predominantly eliminate ammonia through a microtubule network-dependent active NH4+ transport mechanism that is likely performed by cells lining the arterial pockets of the gill lamella where critical Na+/K+-ATPase detection was observed. The V-type H+-ATPase - a vital component to transbranchial ammonia excretion mechanisms of euryhaline crabs - was not found to contribute significantly to ammonia excretion; however, this may be due to the transporter's unexpected apical localization. Although unconnected to ammonia excretion rates, a membrane-bound isoform of carbonic anhydrase was localized to the apical and basolateral membranes of lamella suited for respiration. Urine was found to contain significantly less ammonia as well as carbonate species than the hemolymph, indicating that unlike those of some euryhaline crabs the antennal glands of the Dungeness crab reabsorb these molecules rather than eliminate them for excretion.

Microbiomes of Thalassia testudinum throughout the Atlantic Ocean, Caribbean Sea, and Gulf of Mexico are influenced by site and region while maintaining a core microbiome.

Plant microbiomes are known to serve several important functions for their host, and it is therefore important to understand their composition as well as the factors that may influence these microbial communities. The microbiome of Thalassia testudinum has only recently been explored, and studies to-date have primarily focused on characterizing the microbiome of plants in a single region. Here, we present the first characterization of the composition of the microbial communities of T. testudinum across a wide geographical range spanning three distinct regions with varying physicochemical conditions. We collected samples of leaves, roots, sediment, and water from six sites throughout the Atlantic Ocean, Caribbean Sea, and the Gulf of Mexico. We then analyzed these samples using 16S rRNA amplicon sequencing. We found that site and region can influence the microbial communities of T. testudinum, while maintaining a plant-associated core microbiome. A comprehensive comparison of available microbial community data from T. testudinum studies determined a core microbiome composed of 14 ASVs that consisted mostly of the family Rhodobacteraceae. The most abundant genera in the microbial communities included organisms with possible plant-beneficial functions, like plant-growth promoting taxa, disease suppressing taxa, and nitrogen fixers.

Short-term exposure to high pCO2 leads to decreased branchial cytochrome C oxidase activity in the presence of octopamine in a decapod.

In a recent mechanistic study, octopamine was shown to promote proton transport over the branchial epithelium in green crabs, Carcinus maenas. Here, we follow up on this finding by investigating the involvement of octopamine in an environmental and physiological context that challenges acid-base homeostasis, the response to short-term high pCO2 exposure (400 Pa) in a brackish water environment. We show that hyperregulating green crabs experienced a respiratory acidosis as early as 6 h of exposure to hypercapnia, with a rise in hemolymph pCO2 accompanied by a simultaneous drop of hemolymph pH. The slightly delayed increase in hemolymph HCO3- observed after 24 h helped to restore hemolymph pH to initial values by 48 h. Circulating levels of the biogenic amine octopamine were significantly higher in short-term high pCO2 exposed crabs compared to control crabs after 48 h. Whole animal metabolic rates, intracellular levels of octopamine and cAMP, as well as branchial mitochondrial enzyme activities for complex I + III and citrate synthase were unchanged in posterior gill #7 after 48 h of hypercapnia. However, application of octopamine in gill respirometry experiments suppressed branchial metabolic rate in posterior gills of short-term high pCO2 exposed animals. Furthermore, branchial enzyme activity of cytochrome C oxidase decreased in high pCO2 exposed crabs after 48 h. Our results indicate that hyperregulating green crabs are capable of quickly counteracting a hypercapnia-induced respiratory acidosis. The role of octopamine in the acclimation of green crabs to short-term hypercapnia seems to entail the alteration of branchial metabolic pathways, possibly targeting mitochondrial cytochrome C in the gill. Our findings help advancing our current limited understanding of endocrine components in hypercapnia acclimation. SUMMARY STATEMENT: Acid-base compensation upon short-term high pCO2 exposure in hyperregulating green crabs started after 6 h and was accomplished by 48 h with the involvement of the biogenic amine octopamine, accumulation of hemolymph HCO3-, and regulation of mitochondrial complex IV (cytochrome C oxidase).

Herbivore effects increase with latitude across the extent of a foundational seagrass.

Climate change is altering the functioning of foundational ecosystems. While the direct effects of warming are expected to influence individual species, the indirect effects of warming on species interactions remain poorly understood. In marine systems, as tropical herbivores undergo poleward range expansion, they may change food web structure and alter the functioning of key habitats. While this process ('tropicalization') has been documented within declining kelp forests, we have a limited understanding of how this process might unfold across other systems. Here we use a network of sites spanning 23° of latitude to explore the effects of increased herbivory (simulated via leaf clipping) on the structure of a foundational marine plant (turtlegrass). By working across its geographic range, we also show how gradients in light, temperature and nutrients modified plant responses. We found that turtlegrass near its northern boundary was increasingly affected (reduced productivity) by herbivory and that this response was driven by latitudinal gradients in light (low insolation at high latitudes). By contrast, low-latitude meadows tolerated herbivory due to high insolation which enhanced plant carbohydrates. We show that as herbivores undergo range expansion, turtlegrass meadows at their northern limit display reduced resilience and may be under threat of ecological collapse.

Branchial CO2 and ammonia excretion in crustaceans: Involvement of an apical Rhesus-like glycoprotein.

AIM: To determine whether the crustacean Rh1 protein functions as a dual CO2 /ammonia transporter and investigate its role in branchial ammonia excretion and acid-base regulation. METHODS: Sequence analysis of decapod Rh1 proteins was used to determine the conservation of amino acid residues putatively involved in ammonia transport and CO2 binding in human and bacterial Rh proteins. Using the Carcinus maenas Rh1 protein (CmRh1) as a representative of decapod Rh1 proteins, we test the ammonia and CO2 transport capabilities of CmRh1 through heterologous expression in yeast and Xenopus oocytes coupled with site-directed mutagenesis. Quantitative PCR was used to assess the distribution of CmRh1 mRNA in various tissues. Western blotting was used to assess CmRh1 protein expression changes in response to high environmental ammonia and CO2 . Further, immunohistochemistry was used to assess sub-cellular localization of CmRh1 and a membrane-bound carbonic anhydrase (CmCAg). RESULTS: Sequence analysis of decapod Rh proteins revealed high conservation of several amino acid residues putatively involved in conducting ammonia transport and CO2 binding. Expression of CmRh1 in Xenopus oocytes enhanced both ammonia and CO2 transport which was nullified in CmRh1 D180N mutant oocytes. Transport of the ammonia analog methylamine by CmRh1 is dependent on both ionized and un-ionized ammonia/methylamine species. CmRh1 was co-localized with CmCAg to the apical membrane of the crustacean gill and only experienced decreased protein expression in the anterior gills when exposed to high environmental ammonia. CONCLUSION: CmRh1 is the first identified apical transporter-mediated route for ammonia and CO2 excretion in the crustacean gill. Our findings shed further light on the potential universality of dual ammonia and CO2 transport capacity of Rhesus glycoproteins in both vertebrates and invertebrates.

Improving acute stroke assessment in non-enhanced computed tomography: automated tool for early ischemic lesion volume detection.

BACKGROUND AND OBJECTIVES: ASPECTs is a widely used marker to identify early stroke signs on non-enhanced computed tomography (NECT), yet it presents interindividual variability and it may be hard to use for non-experts. We introduce an algorithm capable of automatically estimating the NECT volumetric extension of early acute ischemic changes in the 3D space. We compared the power of this marker with ASPECTs evaluated by experienced practitioner in predicting the clinical outcome. METHODS: We analyzed and processed neuroimaging data of 153 patients admitted with acute ischemic stroke. All patients underwent a NECT at admission and on follow-up. The developed algorithm identifies the early ischemic hypodense region based on an automatic comparison of the gray level in the images of the two hemispheres, assumed to be an approximate mirror image of each other in healthy patients. RESULTS: In the two standard axial slices used to estimate the ASPECTs, the regions identified by the algorithm overlap significantly with those identified by experienced practitioners. However, in many patients, the regions identified automatically extend significantly to other slices. In these cases, the volume marker provides supplementary and independent information. Indeed, the clinical outcome of patients with volume marker = 0 can be distinguished with higher statistical confidence than the outcome of patients with ASPECTs = 10. CONCLUSION: The volumetric extension and the location of acute ischemic region in the 3D-space, automatically identified by our algorithm, provide data that are mostly in agreement with the ASPECTs value estimated by expert practitioners, and in some cases complementary and independent.

A Preliminary Controlled Trial of Endoscopic Ultrasound-guided Fiducial Markers to Guide Pancreas Surgery.

OBJECTIVE: Endoscopic ultrasound (EUS) is routinely used for fiducial marker placement (FMP) to guide stereotactic radiation of pancreatic tumors, but EUS-FMP explicitly to guide surgery has not been studied in a prospective, controlled manner. Multipurpose EUS systems have been developed that facilitate simultaneous EUS-FMP at the time of biopsy. We aimed to evaluate the feasibility of EUS-FMP to guide pancreatic resection. METHODS: In this prospective trial, we enrolled patients with resectable pancreas masses undergoing tissue sampling and placed preloaded fiducials immediately after biopsy. Intraprocedure confirmation of carcinoma, neuroendocrine, and nonlymphomatous neoplasia by rapid on-site evaluation and lesion size <4 cm was required. The main outcomes were the feasibility and ease of preoperative placement and intraoperative detection of the markers using predefined Likert scales. RESULTS: In 20 patients, EUS-FMP was successful before planned surgery and placement was technically straightforward (Likert Scale: 9.1 ± 1.3; range: 1, most challenging to 10, most facile). Intraoperative detection was feasible and improved when compared with a pre-established comparator of 5 representing an equivalent lesion without a marker (Likert Scale: 7.8 ± 2.2; range: 1, most difficult to 10, most facile; P = 0.011). The mean tumor size on EUS was 1.7 ± 0.9 (range: 0.5 to 3.6) cm. CONCLUSION: EUS-FMP is feasible and safe for resectable pancreatic tumors before surgery and may assist in perioperative detection. Preloaded fiducials may be considered for placement at the time of initial referral for EUS-fine needle biopsy.

ZundEig: The Structure of the Proton in Liquid Water from Unsupervised Learning.

The structure of the excess proton in liquid water has been the subject of lively debate on both experimental and theoretical fronts for the last century. Fluctuations of the proton are typically interpreted in terms of limiting states referred to as the Eigen and Zundel species. Here, we put these ideas under the microscope, taking advantage of recent advances in unsupervised learning that use local atomic descriptors to characterize environments of acidic water combined with advanced clustering techniques. Our agnostic approach leads to the observation of only one charged cluster and two neutral ones. We demonstrate that the charged cluster involving the excess proton is best seen as an ionic topological defect in water's hydrogen bond network, forming a single local minimum on the global free-energy landscape. This charged defect is a highly fluxional moiety, where the idealized Eigen and Zundel species are neither limiting configurations nor distinct thermodynamic states. Instead, the ionic defect enhances the presence of neutral water defects through strong interactions with the network. We dub the combination of the charged and neutral defect clusters as ZundEig, demonstrating that the fluctuations between these local environments provide a general framework for rationalizing more descriptive notions of the proton in the existing literature.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

The carbonyl-lock mechanism underlying non-aromatic fluorescence in biological matter.

Challenging the basis of our chemical intuition, recent experimental evidence reveals the presence of a new type of intrinsic fluorescence in biomolecules that exists even in the absence of aromatic or electronically conjugated chemical compounds. The origin of this phenomenon has remained elusive so far. In the present study, we identify a mechanism underlying this new type of fluorescence in different biological aggregates. By employing non-adiabatic ab initio molecular dynamics simulations combined with a data-driven approach, we characterize the typical ultrafast non-radiative relaxation pathways active in non-fluorescent peptides. We show that the key vibrational mode for the non-radiative decay towards the ground state is the carbonyl elongation. Non-aromatic fluorescence appears to emerge from blocking this mode with strong local interactions such as hydrogen bonds. While we cannot rule out the existence of alternative non-aromatic fluorescence mechanisms in other systems, we demonstrate that this carbonyl-lock mechanism for trapping the excited state leads to the fluorescence yield increase observed experimentally, and set the stage for design principles to realize novel non-invasive biocompatible probes with applications in bioimaging, sensing, and biophotonics.

Complexity of spin configuration dynamics due to unitary evolution and periodic projective measurements.

We study the Hamiltonian dynamics of a many-body quantum system subjected to periodic projective measurements, which leads to probabilistic cellular automata dynamics. Given a sequence of measured values, we characterize their dynamics by performing a principal component analysis (PCA). The number of principal components required for an almost complete description of the system, which is a measure of complexity we refer to as PCA complexity, is studied as a function of the Hamiltonian parameters and measurement intervals. We consider different Hamiltonians that describe interacting, noninteracting, integrable, and nonintegrable systems, including random local Hamiltonians and translational invariant random local Hamiltonians. In all these scenarios, we find that the PCA complexity grows rapidly in time before approaching a plateau. The dynamics of the PCA complexity can vary quantitatively and qualitatively as a function of the Hamiltonian parameters and measurement protocol. Importantly, the dynamics of PCA complexity present behavior that is considerably less sensitive to the specific system parameters for models which lack simple local dynamics, as is often the case in nonintegrable models. In particular, we point out a figure of merit that considers the local dynamics and the measurement direction to predict the sensitivity of the PCA complexity dynamics to the system parameters.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.