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MOTIVATION: Integrative Biomedicl Informatics, Research Program on Biomedical Informatics (IBI - GRIB), Hospital Del Mar Medical Research Institute (IMIM), Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF) C/ del Dr. Aiguader 88 Barcelona 08003 Spain.Understanding the genetic basis of complex diseases is one of the main challenges in modern genomics. However, current tools often lack the versatility to efficiently analyze the intricate relationships between genetic variations and disease outcomes. To address this, we introduce Genopyc, a novel Python library designed for comprehensive investigation of how the variants associated to complex diseases affects downstream pathways. Genopyc offers an extensive suite of functions for heterogeneous data mining and visualization, enabling researchers to delve into and integrate biological information from large-scale genomic datasets. RESULTS: In this work, we present the Genopyc library through application to real-world genome wide association studies variants. Using Genopyc to investigate the functional consequences of variants associated to intervertebral disc degeneration enabled a deeper understanding of the potential dysregulated pathways involved in the disease, which can be explored and visualized by exploiting the functionalities featured in the package. Genopyc emerges as a powerful asset for researchers, facilitating the investigation of complex diseases paving the way for more targeted therapeutic interventions. AVAILABILITY AND IMPLEMENTATION: Genopyc is available on pip https://pypi.org/project/genopyc/.The source code of Genopyc is available at https://github.com/freh-g/genopyc. A tutorial notebook is available at https://github.com/freh-g/genopyc/blob/main/tutorials/Genopyc_tutorial_notebook.ipynb. Finally, a detailed documentation is available at: https://genopyc.readthedocs.io/en/latest/.
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Estudo de Associação Genômica Ampla , Genômica , Software , Humanos , Genômica/métodos , Mineração de Dados/métodos , Variação Genética , Bases de Dados Genéticas , Biologia Computacional/métodosRESUMO
One of the most pressing challenges in genomic medicine is to understand the role played by genetic variation in health and disease. Thanks to the exploration of genomic variants at large scale, hundreds of thousands of disease-associated loci have been uncovered. However, the identification of variants of clinical relevance is a significant challenge that requires comprehensive interrogation of previous knowledge and linkage to new experimental results. To assist in this complex task, we created DisGeNET (http://www.disgenet.org/), a knowledge management platform integrating and standardizing data about disease associated genes and variants from multiple sources, including the scientific literature. DisGeNET covers the full spectrum of human diseases as well as normal and abnormal traits. The current release covers more than 24 000 diseases and traits, 17 000 genes and 117 000 genomic variants. The latest developments of DisGeNET include new sources of data, novel data attributes and prioritization metrics, a redesigned web interface and recently launched APIs. Thanks to the data standardization, the combination of expert curated information with data automatically mined from the scientific literature, and a suite of tools for accessing its publicly available data, DisGeNET is an interoperable resource supporting a variety of applications in genomic medicine and drug R&D.
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Bases de Dados Genéticas , Doença/genética , Loci Gênicos/genética , Variação Genética/genética , Genoma Humano , Mineração de Dados , Genômica , Humanos , Internet , Interface Usuário-ComputadorRESUMO
Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.
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Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Estudos de Casos e Controles , Biologia Computacional/métodos , Europa (Continente)/epidemiologia , Feminino , Ontologia Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Fatores de RiscoRESUMO
The information about the genetic basis of human diseases lies at the heart of precision medicine and drug discovery. However, to realize its full potential to support these goals, several problems, such as fragmentation, heterogeneity, availability and different conceptualization of the data must be overcome. To provide the community with a resource free of these hurdles, we have developed DisGeNET (http://www.disgenet.org), one of the largest available collections of genes and variants involved in human diseases. DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. DisGeNET data are homogeneously annotated with controlled vocabularies and community-driven ontologies. Additionally, several original metrics are provided to assist the prioritization of genotype-phenotype relationships. The information is accessible through a web interface, a Cytoscape App, an RDF SPARQL endpoint, scripts in several programming languages and an R package. DisGeNET is a versatile platform that can be used for different research purposes including the investigation of the molecular underpinnings of specific human diseases and their comorbidities, the analysis of the properties of disease genes, the generation of hypothesis on drug therapeutic action and drug adverse effects, the validation of computationally predicted disease genes and the evaluation of text-mining methods performance.
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Biologia Computacional/métodos , Bases de Dados Genéticas , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Variação Genética , Genômica/métodos , Humanos , Software , NavegadorRESUMO
MOTIVATION: DisGeNET-RDF makes available knowledge on the genetic basis of human diseases in the Semantic Web. Gene-disease associations (GDAs) and their provenance metadata are published as human-readable and machine-processable web resources. The information on GDAs included in DisGeNET-RDF is interlinked to other biomedical databases to support the development of bioinformatics approaches for translational research through evidence-based exploitation of a rich and fully interconnected linked open data. AVAILABILITY AND IMPLEMENTATION: http://rdf.disgenet.org/ CONTACT: support@disgenet.org.
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Biologia Computacional , Doença/genética , Semântica , Bases de Dados Factuais , Humanos , InternetRESUMO
UNLABELLED: PsyGeNET (Psychiatric disorders and Genes association NETwork) is a knowledge platform for the exploratory analysis of psychiatric diseases and their associated genes. PsyGeNET is composed of a database and a web interface supporting data search, visualization, filtering and sharing. PsyGeNET integrates information from DisGeNET and data extracted from the literature by text mining, which has been curated by domain experts. It currently contains 2642 associations between 1271 genes and 37 psychiatric disease concepts. In its first release, PsyGeNET is focused on three psychiatric disorders: major depression, alcohol and cocaine use disorders. PsyGeNET represents a comprehensive, open access resource for the analysis of the molecular mechanisms underpinning psychiatric disorders and their comorbidities. AVAILABILITY AND IMPLEMENTATION: The PysGeNET platform is freely available at http://www.psygenet.org/. The PsyGeNET database is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0/). CONTACT: lfurlong@imim.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Alcoolismo/genética , Biomarcadores/análise , Transtornos Relacionados ao Uso de Cocaína/genética , Transtorno Depressivo Maior/genética , Redes Reguladoras de Genes , Bases de Conhecimento , Software , Algoritmos , Animais , Mapeamento Cromossômico , Mineração de Dados , Bases de Dados Factuais , Modelos Animais de Doenças , Humanos , Camundongos , Publicações , RatosRESUMO
BACKGROUND: Current biomedical research needs to leverage and exploit the large amount of information reported in scientific publications. Automated text mining approaches, in particular those aimed at finding relationships between entities, are key for identification of actionable knowledge from free text repositories. We present the BeFree system aimed at identifying relationships between biomedical entities with a special focus on genes and their associated diseases. RESULTS: By exploiting morpho-syntactic information of the text, BeFree is able to identify gene-disease, drug-disease and drug-target associations with state-of-the-art performance. The application of BeFree to real-case scenarios shows its effectiveness in extracting information relevant for translational research. We show the value of the gene-disease associations extracted by BeFree through a number of analyses and integration with other data sources. BeFree succeeds in identifying genes associated to a major cause of morbidity worldwide, depression, which are not present in other public resources. Moreover, large-scale extraction and analysis of gene-disease associations, and integration with current biomedical knowledge, provided interesting insights on the kind of information that can be found in the literature, and raised challenges regarding data prioritization and curation. We found that only a small proportion of the gene-disease associations discovered by using BeFree is collected in expert-curated databases. Thus, there is a pressing need to find alternative strategies to manual curation, in order to review, prioritize and curate text-mining data and incorporate it into domain-specific databases. We present our strategy for data prioritization and discuss its implications for supporting biomedical research and applications. CONCLUSIONS: BeFree is a novel text mining system that performs competitively for the identification of gene-disease, drug-disease and drug-target associations. Our analyses show that mining only a small fraction of MEDLINE results in a large dataset of gene-disease associations, and only a small proportion of this dataset is actually recorded in curated resources (2%), raising several issues on data prioritization and curation. We propose that joint analysis of text mined data with data curated by experts appears as a suitable approach to both assess data quality and highlight novel and interesting information.
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Mineração de Dados/métodos , Doença/genética , Armazenamento e Recuperação da Informação , MEDLINE , Publicações , Pesquisa Translacional Biomédica , Bases de Dados Factuais , Depressão/genética , Doença/classificação , Humanos , Bases de ConhecimentoRESUMO
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often suffer concomitant disorders that worsen significantly their health status and vital prognosis. The pathogenic mechanisms underlying COPD multimorbidities are not completely understood, thus the exploration of potential molecular and biological linkages between COPD and their associated diseases is of great interest. METHODS: We developed a novel, unbiased, integrative network medicine approach for the analysis of the diseasome, interactome, the biological pathways and tobacco smoke exposome, which has been applied to the study of 16 prevalent COPD multimorbidities identified by clinical experts. RESULTS: Our analyses indicate that all COPD multimorbidities studied here are related at the molecular and biological level, sharing genes, proteins and biological pathways. By inspecting the connections of COPD with their associated diseases in more detail, we identified known biological pathways involved in COPD, such as inflammation, endothelial dysfunction or apoptosis, serving as a proof of concept of the methodology. More interestingly, we found previously overlooked biological pathways that might contribute to explain COPD multimorbidities, such as hemostasis in COPD multimorbidities other than cardiovascular disorders, and cell cycle pathway in the association of COPD with depression. Moreover, we also observed similarities between COPD multimorbidities at the pathway level, suggesting common biological mechanisms for different COPD multimorbidities. Finally, chemicals contained in the tobacco smoke target an average of 69% of the identified proteins participating in COPD multimorbidities. CONCLUSIONS: The network medicine approach presented here allowed the identification of plausible molecular links between COPD and comorbid diseases, and showed that many of them are targets of the tobacco exposome, proposing new areas of research for understanding the molecular underpinning of COPD multimorbidities.
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Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Biologia de Sistemas , Comorbidade , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Nível de Saúde , Humanos , Prevalência , Prognóstico , Mapas de Interação de Proteínas , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Transdução de Sinais , Fumaça/efeitos adversos , Fumar/efeitos adversos , Integração de SistemasRESUMO
Knowledge graph embeddings (KGE) are a powerful technique used in the biomedical domain to represent biological knowledge in a low dimensional space. However, a deep understanding of these methods is still missing, and, in particular, regarding their applications to prioritize genes associated with complex diseases with reduced genetic information. In this contribution, we built a knowledge graph (KG) by integrating heterogeneous biomedical data and generated KGE by implementing state-of-the-art methods, and two novel algorithms: Dlemb and BioKG2vec. Extensive testing of the embeddings with unsupervised clustering and supervised methods showed that KGE can be successfully implemented to predict genes associated with diseases and that our novel approaches outperform most existing algorithms in both scenarios. Our findings underscore the significance of data quality, preprocessing, and integration in achieving accurate predictions. Additionally, we applied KGE to predict genes linked to Intervertebral Disc Degeneration (IDD) and illustrated that functions pertinent to the disease are enriched within the prioritized gene set.
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Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions.
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Sistemas de Gerenciamento de Base de Dados , Bases de Dados Factuais , Documentação/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Armazenamento e Recuperação da Informação/métodos , Sistema de Registros , Simulação por Computador , Humanos , Modelos BiológicosRESUMO
Introduction: Network-based methods are promising approaches in systems toxicology because they can be used to predict the effects of drugs and chemicals on health, to elucidate the mode of action of compounds, and to identify biomarkers of toxicity. Over the years, the network biology community has developed a wide range of methods, and users are faced with the task of choosing the most appropriate method for their own application. Furthermore, the advantages and limitations of each method are difficult to determine without a proper standard and comparative evaluation of their performance. This study aims to evaluate different network-based methods that can be used to gain biological insight into the mechanisms of drug toxicity, using valproic acid (VPA)-induced liver steatosis as a benchmark. Methods: We provide a comprehensive analysis of the results produced by each method and highlight the fact that the experimental design (how the method is applied) is relevant in addition to the method specifications. We also contribute with a systematic methodology to analyse the results of the methods individually and in a comparative manner. Results: Our results show that the evaluated tools differ in their performance against the benchmark and in their ability to provide novel insights into the mechanism of adverse effects of the drug. We also suggest that aggregation of the results provided by different methods provides a more confident set of candidate genes and processes to further the knowledge of the drug's mechanism of action. Discussion: By providing a detailed and systematic analysis of the results of different network-based tools, we aim to assist users in making informed decisions about the most appropriate method for systems toxicology applications.
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The use of molecular biomarkers to support disease diagnosis, monitor its progression, and guide drug treatment has gained traction in the last decades. While only a dozen biomarkers have been approved for their exploitation in the clinic by the FDA, many more are evaluated in the context of translational research and clinical trials. Furthermore, the information on which biomarkers are measured, for which purpose, and in relation to which conditions are not readily accessible: biomarkers used in clinical studies available through resources such as ClinicalTrials.gov are described as free text, posing significant challenges in finding, analyzing, and processing them by both humans and machines. We present a text mining strategy to identify proteomic and genomic biomarkers used in clinical trials and classify them according to the methodologies by which they are measured. We find more than 3000 biomarkers used in the context of 2600 diseases. By analyzing this dataset, we uncover patterns of use of biomarkers across therapeutic areas over time, including the biomarker type and their specificity. These data are made available at the Clinical Biomarker App at https://www.disgenet.org/biomarkers/, a new portal that enables the exploration of biomarkers extracted from the clinical studies available at ClinicalTrials.gov and enriched with information from the scientific literature. The App features several metrics that assess the specificity of the biomarkers, facilitating their selection and prioritization. Overall, the Clinical Biomarker App is a valuable and timely resource about clinical biomarkers, to accelerate biomarker discovery, development, and application.
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Introduction: Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. Methods: In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. Results: We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. Discussion: In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.
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We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic-induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial-related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse-specific version of the model to quantify doxorubicin and 5-fluorouracil (5-FU)-induced toxicity, which included pharmacokinetics and 5-FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose-dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk, and transcriptional induction of the p53 pathway. Using a human-specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5-FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific-molecularly targeted therapy, the mice failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modeling approach, preclinical experimental settings have to be suitable to quantify drug-induced clinical toxicity with precision at the structural scale of the model. Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross-settings differences in toxicity when building these approaches.
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Citrulina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Camundongos , Humanos , Animais , Fluoruracila/toxicidade , Fluoruracila/metabolismo , Mucosa Intestinal/metabolismo , Diarreia/induzido quimicamente , Doxorrubicina/toxicidadeRESUMO
Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors. Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.
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COVID-19 , Humanos , SARS-CoV-2 , Reposicionamento de Medicamentos , Biologia de Sistemas , Simulação por ComputadorRESUMO
Our knowledge of complex disorders has increased in the last years thanks to the identification of genetic variants (GVs) significantly associated with disease phenotypes by genome-wide association studies (GWAS). However, we do not understand yet how these GVs functionally impact disease pathogenesis or their underlying biological mechanisms. Among the multiple post-GWAS methods available, fine-mapping and colocalization approaches are commonly used to identify causal GVs, meaning those with a biological effect on the trait, and their functional effects. Despite the variety of post-GWAS tools available, there is no guideline for method eligibility or validity, even though these methods work under different assumptions when accounting for linkage disequilibrium and integrating molecular annotation data. Moreover, there is no benchmarking of the available tools. In this context, we have applied two different fine-mapping and colocalization methods to the same GWAS on major depression (MD) and expression quantitative trait loci (eQTL) datasets. Our goal is to perform a systematic comparison of the results obtained by the different tools. To that end, we have evaluated their results at different levels: fine-mapped and colocalizing GVs, their target genes and tissue specificity according to gene expression information, as well as the biological processes in which they are involved. Our findings highlight the importance of fine-mapping as a key step for subsequent analysis. Notably, the colocalizing variants, altered genes and targeted tissues differed between methods, even regarding their biological implications. This contribution illustrates an important issue in post-GWAS analysis with relevant consequences on the use of GWAS results for elucidation of disease pathobiology, drug target prioritization and biomarker discovery.
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Understanding the molecular basis of major depression is critical for identifying new potential biomarkers and drug targets to alleviate its burden on society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of major depression-associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with major depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis and alteration of transcription factor binding sites. The fine-mapping process uncovered putative causally associated variants whose proximal genes were linked with major depression pathophysiology. Four colocalizing genetic variants altered the expression of five genes, highlighting the role of SLC12A5 in neuronal chlorine homeostasis and MYRF in nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of rs62259947 in modulating P4HTM expression by altering the YY1 binding site, altogether regulating hypoxia response. Overall, our pipeline could prioritize putative causal genetic variants in major depression. More importantly, it can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.
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Transtorno Depressivo Maior , Locos de Características Quantitativas , Depressão , Transtorno Depressivo Maior/genética , Genômica , Humanos , Fatores de Transcrição/genéticaRESUMO
Thanks to the unbiased exploration of genomic variants at large scale, hundreds of thousands of disease-associated loci have been uncovered. In parallel, network-based approaches have proven to be essential to understand the molecular mechanisms underlying human diseases. The use of these approaches has been boosted by the abundance of information about disease associated genes and variants, high quality human interactomics data, and the emergence of new types of omics data. The DisGeNET Cytoscape App combines the capabilities of Cytoscape with those of DisGeNET, a knowledge platform based on a comprehensive catalogue of disease-associated genes and variants. The DisGeNET Cytoscape App contains functions to query, analyze, and visualize different network representations of the gene-disease and variant-disease associations available in DisGeNET. It supports a wide variety of applications through its query and filter functionalities, including the annotation of foreign networks generated by other apps or uploaded by the user. The new release of the DisGeNET Cytoscape App has been designed to support Cytoscape 3.x and incorporates novel distinctive features such as visualization and analysis of variant-disease networks, disease enrichment analysis for genes and variants, and analytic support through Cytoscape Automation. Moreover, the DisGeNET Cytoscape App features an API to access its core functionalities via the REST protocol fostering the development of reproducible and scalable analysis workflows based on DisGeNET data.
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BACKGROUND: Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer's disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown. METHODS: We investigated the cognitive and emotional behavioural responses in 3- and 6-month-old APP/PSEN1-Tg mice, before ß-amyloid plaques were detected. We studied the genetic and pathway deregulation in the prefrontal cortex, striatum, hippocampus and amygdala of mice at both ages, using transcriptomic and functional data analysis. RESULTS: We found that depressive-like and anxiety-like behaviours, as well as memory impairments, are already present at 3-month-old APP/PSEN1-Tg mutant mice together with the deregulation of several genes, such as Ciart, Grin3b, Nr1d1 and Mc4r, and other genes including components of the circadian rhythms, electron transport chain and neurotransmission in all brain areas. Extending these results to human data performing GSEA analysis using DisGeNET database, it provides translational support for common deregulated gene sets related to MD and AD. CONCLUSIONS: The present study sheds light on the shared genetic bases between MD and AD, based on a comprehensive characterization from the behavioural to transcriptomic level. These findings suggest that late MD could be an early manifestation of AD.
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Doença de Alzheimer , Transtorno Depressivo Maior , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Comorbidade , Depressão , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , TranscriptomaRESUMO
OBJECTIVES: SARS-CoV-2 infection induces virus-reactive memory B cells expressing unmutated antibodies, which hints at their emergence from naïve B cells. Yet, the dynamics of virus-specific naïve B cells and their impact on immunity and immunopathology remain unclear. METHODS: We longitudinally profiled SARS-CoV-2-specific B-cell responses in 25 moderate-to-severe COVID-19 patients by high-dimensional flow cytometry and isotyping and subtyping ELISA. We also explored the relationship of B-cell responses to SARS-CoV-2 with the activation of effector and regulatory cells from the innate or adaptive immune system. RESULTS: We found a virus-specific antibody response with a broad spectrum of classes and subclasses during acute infection, which evolved into an IgG1-dominated response during convalescence. Acute infection was associated with increased mature B-cell progenitors in the circulation and the unexpected expansion of virus-targeting naïve-like B cells. The latter further augmented during convalescence together with virus-specific memory B cells. In addition to a transitory increase in tissue-homing CXCR3+ plasmablasts and extrafollicular memory B cells, most COVID-19 patients showed persistent activation of CD4+ and CD8+ T cells along with transient or long-lasting changes of key innate immune cells. Remarkably, virus-specific antibodies and the frequency of naïve B cells were among the major variables defining distinct immune signatures associated with disease severity and inflammation. CONCLUSION: Aside from providing new insights into the complexity of the immune response to SARS-CoV-2, our findings indicate that the de novo recruitment of mature B-cell precursors into the periphery may be central to the induction of antiviral immunity.