Biology subjects

John, S.

Publications and source records attributed to John, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Electrocatalytic on-site oxygenation for transplanted cell-based-therapies

Implantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant host1, 2. Exogenous oxygen production can support cells and tissues, such as pancreatic islets and engineered therapeutic cells. Previous oxygenation strategies have targeted gas circulation or decomposition of solid peroxides. These strategies however require bulky implants, transcutaneous supply lines, and are limited in their total oxygen production or regulation3, 4. Readily integrated and controlled production of oxygen has eluded cell therapy devices. Here, we show an electrocatalytic approach that enables bioelectronic control of oxygen generation in complex cellular environments to sustain engineered cell viability and therapy production under hypoxic stress and at high cell densities. Nanostructured sputtered iridium oxide serves as an ideal catalyst for oxygen evolution reaction (OER) at neutral pH. It enables a lower OER onset and shows selective oxygen production without evolution of toxic side products over a 300 mV window of operation. This electrocatalytic on site oxygenator (ecO2) can sustain high cell loadings (>60k cells/mm3) in hypoxic conditions in vitro and in vivo. Our results demonstrate that exogenous oxygen production devices can be readily integrated into bioelectronic platforms and enable high cell loadings in smaller device footprints with broad applicability.

bioengineering↗

bioRxiv2023

Zoledronic acid improves bone quality and muscle function in a high bone turnover state

SUMMARYZoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGF{beta} release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease. Context and significanceTGF{beta} is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGF{beta} causes several bone disorders and skeletal muscle weakness. Reducing excess TGF{beta} release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acids benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.

cancer biology↗

bioRxiv2023

Cardiac Effects of a Novel pH-Insensitive Sodium-Calcium Exchanger Mouse

BACKGROUNDCardiac sodium-calcium exchange (NCX1) is the dominant calcium (Ca) efflux mechanism in cardiomyocytes and is strongly regulated by pH. However, the role of NCX1 pH sensitivity in normal cardiac function is unknown. METHODSWe used CRISPR/Cas9 to produce a pH-resistant NCX1 mouse by replacing the histidine at position 165 of NCX1 with an alanine (H165A). Hearts were studied using echocardiography and ECG. RNA and protein expression levels were assessed using qPCR and Western blotting. Isolated ventricular cardiomyocytes were loaded with Ca indicators and patch clamped to record intracellular Ca transients and membrane current and voltage. RESULTSH165A mice live into adulthood with slightly reduced LV systolic function, normal heart rate and shortened QT interval. Both male and female animals exhibit reduced growth, but females eventually reach normal body weight. In patch clamped myocytes, NCX current (INCX) evoked by voltage ramps was reduced by 35% (at +80 mV). Lowering pHi to 6.5 using Na-Acetate had no effect on INCX in H165A myocytes, whereas the same intervention in wildtype (WT) inhibited INCX by 69% (at +80 mV, p<0.01). There was no change in H165A ventricular cardiomyocyte Ca transients measured with fura-2 AM. However, action potential duration was reduced 68%, consistent with the shorter QT interval. This coincided with a 37% reduction in L-type Ca current and increased expression of repolarizing K+ channels. H165A mice are also resistant to ischemia/reperfusion injury. CONCLUSIONSThe H165A mutation attenuates pH regulation of NCX1 in mice, is associated with reduced growth and accelerates cardiac repolarization without compromising excitation-contraction coupling. The mutation also confers cardioprotection. The H165A mouse is the first evidence that pH regulation of NCX1 affects cardiac physiology and is a potential model for studying the role of NCX1 pH-sensitivity on both physiological and pathophysiological cardiac function.

biophysics↗

bioRxiv2023

HIV-differentiated metabolite N-Acetyl-L-Alanine dysregulates human natural killer cell responses to Mycobacterium tuberculosis infection

BackgroundMycobacterium tuberculosis (Mtb) has latently infected over two billion people worldwide (LTBI) and causes 1.8 million deaths each year. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of developing active tuberculosis by 10-20 times compared to the HIV-LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals. MethodsPlasma samples collected from healthy and HIV-infected individuals were investigated by liquid chromatography-mass spectrometry (LC-MS), and the metabolic data were analyzed using an online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, quantitative reverse transcription PCR (qRT-PCR) were performed by standard procedure to determine the surface markers, cytokines and other signaling molecule expression. Seahorse extra cellular flux assays were used to measure the mitochondrial oxidative phosphorylation and glycolysis. ResultsSix metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared to healthy donors. One of the HIV-upregulated metabolites, N-Acetyl-L-Alanine (ALA), inhibits pro-inflammatory cytokine IFN-{square} production by NK cells of LTBI+ individuals. ALA inhibits glycolysis of LTBI+ individuals NK cells in response to Mtb. ConclusionsOur findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK cell-mediated immune responses to Mtb infection, offering a new understanding of the HIV-Mtb interaction and providing the implication of nutrition intervention and therapy for HIV-Mtb co-infected patients.

immunology↗

bioRxiv2022

Transcription factor HSFA7b controls ethylene signaling and meristem maintenance at the shoot apical meristem during thermomemory

The shoot apical meristem (SAM) is responsible for overall shoot growth by generating all above-ground structures. Recent research identified that the SAM displays an autonomous heat stress (HS) memory of a previous non-lethal HS event. Considering the importance of the SAM for plant growth it is essential to unlock how its thermomemory is mechanistically controlled. Here, we report that HEAT SHOCK TRANSCRIPTION FACTOR A7b (HSFA7b) plays a crucial role in this process in Arabidopsis. We found that HSFA7b directly regulates ethylene response at the SAM by binding to promoters of key regulators of ethylene signaling including ETHYLENE-INSENSITIVE 3 to establish thermotolerance. Moreover, HSFA7b controls maintenance of the SAM stem cell pool during thermomemory by regulating the expression of the master regulator WUSCHEL through direct transcriptional activation of the SPLAYED chromatin remodelling factor.

plant biology↗

bioRxiv2021

Mouse models of NADK2 deficiency analyzed for metabolic and gene expression changes to elucidate pathophysiology

NADK2 encodes the mitochondrial isoform of NAD Kinase, which phosphorylates nicotinamide adenine dinucleotide (NAD). Rare recessive mutations in human NADK2 are associated with a syndromic neurological mitochondrial disease that includes metabolic changes such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, the full pathophysiology resulting from NADK2 deficiency is not known. Here we describe two chemically-induced mouse mutations in Nadk2, S326L and S330P, which cause a severe neuromuscular disease and shorten lifespan. The S330P allele was characterized in detail and shown to have marked denervation of neuromuscular junctions by 5 weeks of age and muscle atrophy by 11 weeks of age. Cerebellar Purkinje cells also showed progressive degeneration in this model. Transcriptome profiling on brain and muscle was performed at early and late disease stages. In addition, metabolomic profiling was performed on brain, muscle, liver, and spinal cord at the same ages. Combined transcriptomic and metabolomic analyses identified hyperlysinemia, DECR deficiency, and generalized metabolic dysfunction in Nadk2 mutant mice, indicating relevance to the human disease. We compared findings from the Nadk model to equivalent RNAseq and metabolomic datasets from a mouse model of infantile neuroaxonal dystrophy, caused by recessive mutations in Pla2g6. This enabled us to identify disrupted biological processes that are common between these mouse models of neurological disease, such as translation, and those processes that are gene-specific such as glycolysis and acetylcholine binding. These findings improve our understanding of the pathophysiology of both Nadk2 and Pla2g6 mutations, as well as pathways common to neuromuscular/neurodegenerative diseases.

genetics↗

bioRxiv2021

OmicsView: omics data analysis through interactive visual analytics

With advances in NGS technologies, transcriptional profiling of human tissue across many diseases is becoming more routine, leading to the generation of petabytes of data deposited in public repositories. There is a need for bench scientists with little computational expertise to be able to access and mine this data to understand disease pathology, identify robust biomarkers of disease and the effect of interventions (in vivo or in vitro). To this end we release an open source analytics and visualization platform for expression data called OmicsView, http://omicsview.org. This platform comes preloaded with 1000s of samples across many disease areas and normal tissue, including the GTEx database, all processed with a harmonized pipeline. We demonstrate the power and ease-of-use of the platform by means of a Crohns disease data mining exercise where we can quickly uncover disease pathology and identify strong biomarkers of disease and response to treatment.

bioinformatics↗

bioRxiv2021

Nitrogen fixation in mesoscale eddies of the North Pacific Subtropical Gyre: patterns and mechanisms

1.Mesoscale eddies have been shown to support elevated dinitrogen (N2) fixation rates (NFRs) and abundances of N2-fixing microorganisms (diazotrophs), but the mechanisms underlying these observations are not well understood. We explored relationships among NFRs and cyanobacterial diazotroph abundances in eddy pairs of opposite polarity sampled in the North Pacific Subtropical Gyre and compared our observations to seasonal trends from the Hawaii Ocean Time-series (HOT) program. Consistent with previous reports, we found that NFRs were anomalously high for this region (up to 3.7-fold above previous monthly HOT observations) in the centers of the sampled anticyclones, coinciding with elevated abundances of Crocosphaera in the summertime. We then coupled our field-based observations, together with transcriptomic analyses of nutrient stress marker genes and ecological models, to evaluate potential mechanisms controlling diazotroph abundance and activity at the mesoscale. Specifically, we evaluated the role of biological (via estimates of growth and grazing rates) and physical controls on populations of Crocosphaera, Trichodesmium, and diatom symbionts. Our results suggest that increased Crocosphaera abundances associated with summertime anticyclones resulted from the alleviation of phosphate limitation, allowing cells to grow at rates exceeding grazing losses. In contrast, distributions of larger, buoyant taxa (Trichodesmium and diatom symbionts) appeared less affected by eddy-driven biological controls. Instead, they appeared driven by physical dynamics along frontal boundaries that separate cyclonic and anticyclonic eddies. Together, the interplay of eddy-specific changes in bottom-up control, top-down control, and the physical accumulation of cells likely explains the elevated diazotroph abundances and NFRs associated with anticyclones and eddy fronts.

ecology↗

bioRxiv2021

Hepatocyte nuclear factor 4a and glucocorticoid receptor coordinately regulate lipid metabolism in mice fed a high-fat-high-sugar diet

Hepatocyte nuclear factor 4 (HNF4) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study was aimed to elucidate the role of down-regulation of HNF4 and GR in fatty liver and hyperlipidemia. Adult mice with liver-specific heterozygote and knockout (knockout) of HNF4 were fed a low-fat diet (LFD) or a high-fat-high-sugar diet (HFHS) for 15 days. Compared to LFD-fed mice, HFHS-fed wildtype mice had hepatic induction of lipid catabolic genes and down-regulation of lipogenic genes. Compared to HFHS-fed wildtype mice, HNF4 heterozygote mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4 knockout mice had mild hypolipidemia, down-regulation of lipid-efflux genes, but induction of genes for uptake/storage of lipids. Sterol-regulatory-element-binding protein-1c (SREBP-1C), a master lipogenic regulator, was induced in HFHS-fed HNF4 heterozygote mice. In reporter assays, HNF4 potently inhibited the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Surprisingly, nuclear GR proteins were gene-dosage-dependently decreased in HNF4 heterozygote and knockout mice. HFHS-fed mice with liver-specific knockout of GR had increased hepatic lipids and induction of SREBP-1C and PPAR{gamma}. In reporter assays, GR and HNF4 synergistically/additively induced lipid catabolic genes. Phosphorylation of AMP-activated protein kinase (AMPK), a key GR modulator, was dramatically decreased in HNF4 knockout mice. Thus, cooperative induction of lipid catabolic genes and suppression of lipogenic genes by HNF4 and GR, modulated by AMPK, may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.

molecular biology↗

bioRxiv2020

Functional Aspects of the Eustachian Tube by Means of 3D-Modeling

The extent of dysfunction of the Eustachian tube (ET) is relevant in understanding the pathogenesis of secondary otological diseases such as acute or chronic otitis media. The underlying mechanism of ET dysfunction remains poorly understood except for an apparent genesis such as a nasopharyngeal tumor or cleft palate. To better describe the ET, its functional anatomy, and the biomechanical valve mechanism and subsequent development of diagnostic and interventional tools, a three-dimensional model based on thin-layer histology was created from an ET in this study. Blackface sheep was chosen as a donor. The 3-D model was generated by the coherent alignment of the sections. It was then compared with the cone-beam computed tomography dataset of the complete embedded specimen taken before slicing. The model shows the topographic relation of the individual components, such as the bone and cartilage, the muscles and connective tissue, as well as the lining epithelium with the lumen. It indicates a limited spiraling rotation of the cartilaginous tube over its length and relevant positional relationships of the tensor and levator veli palatine muscles.

physiology↗

bioRxiv2020

Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

Colorectal cancers (CRCs) show variable response to immune checkpoint blockade, which can only partially be explained by the variability of tumour mutational burden. To dissect the cellular and molecular determinants of response we performed a multi-omic screen of 721 cancer regions from patients treated with Pembrolizumab (KEYNOTE 177 clinical trial) or Nivolumab. Multi-regional whole exome, RNA and T-cell receptor sequencing show that, within hypermutated CRCs, response to both anti-PD1 agents is not positively associated with tumour mutational burden but with high clonality of immunogenic mutations, expanded T cells, low activation of the WNT pathway and active immune escape mechanisms. Coupling high-dimensional imaging mass cytometry with multiplexed immunofluorescence and computational spatial analysis, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 cells interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting cytotoxic anti-tumour activity.

cancer biology↗

bioRxiv2020

Preliminary Minimum Reporting Requirements for Reporting In-Vivo Neural Interface Research: I. Implantable Neural Interfaces

The pace of research and development in neuroscience, neurotechnology, and neurorehabilitation is rapidly accelerating, with the number of publications doubling every 4.2 years. Maintaining this progress requires technological standards and scientific reporting guidelines to provide frameworks for communication and interoperability. The present lack of such standards for neurotechnologies limits the transparency, reproducibility, and meta-analysis of this growing body of research, posing an ongoing barrier to research, clinical, and commercial objectives. Continued neurotechnological innovation requires the development of some minimal standards to promote integration between this broad spectrum of technologies and therapies. To preserve design freedom and accelerate the translation of research into safe and effective technologies with maximal user benefit, such standards must be collaboratively co-developed by a full spectrum of neuroscience and neurotechnology stakeholders. This paper summarizes the preliminary recommendations of IEEE Working Group P2794, developing a Reporting Standard for in-vivo Neural Interface Research (RSNIR). Impact StatementThis work provides a preliminary set of reporting guidelines for implantable neural interface research, developed by IEEE WG P2794 in open collaboration between a range of stakeholders to accelerate the research, development, and integration of innovative neurotechnologies.

bioengineering↗

bioRxiv2020

Pairwise genetic interactions modulate lipid plasma levels and cellular uptake

Genetic interactions (GIs), the joint impact of different genes or variants on a phenotype, are foundational to the genetic architecture of complex traits. However, identifying GIs through human genetics is challenging since it necessitates very large population sizes, while findings from model systems not always translate to humans. Here, we combined exome-sequencing and genotyping in the UK Biobank with combinatorial RNA-interference (coRNAi) screening to systematically test for pairwise GIs between 30 lipid GWAS genes. Gene-based protein-truncating variant (PTV) burden analyses from 240,970 exomes revealed additive GIs for APOB with PCSK9 and LPL, respectively. Both, genetics and coRNAi identified additive GIs for 12 additional gene pairs. Overlapping non-additive GIs were detected only for TOMM40 at the APOE locus with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate both, plasma and cellular lipid levels via additive and non-additive effects and nominates drug target pairs for improved lipid-lowering combination therapies.

genetics↗

bioRxiv2020

Human marginal zone B cell development from early T2 progenitors

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2 and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of 4{beta}7 integrin and lower expression of IL4 receptor (IL4R) compared to the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZB). Lineage progression from T1 cells to MZB via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut homing T2 cells is observed in severe SLE and is associated with reduction of MZB and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence and importance for maintaining health.

cell biology↗

bioRxiv2020

Non-parametric modelling of temporal and spatial counts data from RNA-seq experiments

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSMotivationC_ST_ABSThe negative binomial distribution has been shown to be a good model for counts data from both bulk and single-cell RNA-sequencing (RNA-seq). Gaussian process (GP) regression provides a useful non-parametric approach for modeling temporal or spatial changes in gene expression. However, currently available GP regression methods that implement negative binomial likelihood models do not scale to the increasingly large datasets being produced by single-cell and spatial transcriptomics. ResultsThe GPcounts package implements GP regression methods for modelling counts data using a negative binomial likelihood function. Computational efficiency is achieved through the use of variational Bayesian inference. The GP function models changes in the mean of the negative binomial likelihood through a logarithmic link function and the dispersion parameter is fitted by maximum likelihood. We validate the method on simulated time course data, showing that it is better able to identify changes in over-dispersed counts data than methods based on Gaussian or Poisson likelihoods. To demonstrate temporal inference, we apply GPcounts to single-cell RNA-seq datasets after pseudotime and branching inference. To demonstrate spatial inference, we apply GPcounts to data from the mouse olfactory bulb to identify spatially variable genes and compare to two published GP methods. We also provide the option of modelling additional dropout using a zero-inflated negative binomial. Our results show that GPcounts can be used to model temporal and spatial counts data in cases where simpler Gaussian and Poisson likelihoods are unrealistic. AvailabilityGPcounts is implemented using the GPflow library in Python and is available at https://github.com/ManchesterBioinference/GPcounts along with the data, code and notebooks required to reproduce the results presented here. Contactnuha.bintayyash@manchester.ac.uk or magnus.rattray@manchester.ac.uk

bioinformatics↗

bioRxiv2020

STIL a novel link in Shh and Wnt signaling, endowing oncogenic and stem like attributes to colorectal cancer

Discovery of potent gene regulating tumorigenesis and drug resistance is of high clinical importance. STIL is an oncogene, however its molecular insights and role in colorectal oncogenesis are unknown. In this study we have explored role of STIL in tumorigenesis and studied its molecular targets in colorectal cancer (CRC). STIL silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers CD133 & CD44 and drug resistant markers Thymidylate synthase, ABCB1 & ABCG2 both in in-vitro and in-vivo CRC models. In addition, over expression of STIL mRNA was found to be associated with reduced disease free survival in CRC cases. To our surprise we observed an Shh independent regulation of stemness and drug resistant genes mediated by STIL. Interestingly, we found an Shh independent regulation of {beta}-catenin mediated by STIL via p-AKT, which partially answers Shh independent regulatory mechanism of CSC markers by STIL. Our study suggest an instrumental role of STIL in molecular manifestation of CRC and progression.

cancer biology↗

bioRxiv2020

An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner1,2. Excessive complement and IFN-{gamma}-associated responses are known drivers of immunopathogenesis3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection4. The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-{gamma} producing CD4+ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-{gamma}+ Th1 cells to suppressive IL-10+ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor5-7. Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4+ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4+ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.

immunology↗

bioRxiv2020

The burden of rare protein-truncating genetic variants on human lifespan

Genetic predisposition is believed to contribute substantially to the age at which we die. Genome-wide association studies (GWAS) have implicated more than 20 genetic loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss-of-function. Through whole-exome sequencing of 238,239 UK Biobank participants, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified exome-wide (P<2.5e-6) significant associations between BRCA2, BRCA1, TET2, PPM1D, LDLR, EML2 and DEDD2 PTV-burden with human lifespan. Gene and gene-set PTV-burden phenome-wide association studies (PheWAS) further highlighted the roles of these genes in cancer and cardiovascular disease as relevant for overall survival. The overlap between PTV-burden and prior GWAS results was modest, underscoring the value of sequencing in well-powered cohorts to complement GWAS for identifying loci associated with complex traits and disease.

genetics↗