Browsing by Author "Vicente, Astrid Moura"
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- Análise de uma rede de similaridade genética entre a perturbação do espetro do autismo e comorbilidades do foro neurológico e neuropsiquiátricoPublication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João Xavier; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid MouraA Perturbação do Espetro do Autismo (PEA) é uma perturbação do neurodesenvolvimento com apresentação clínica heterogénea, nível de gravidade variável e ocorrência de múltiplas comorbilidades. A PEA tem uma arquitetura genética complexa que se reflete na sua heterogeneidade clínica, existindo evidência de uma sobreposição de genes alterados entre esta condição e diversas comorbilidades do foro neurológico e neuropsiquiátrico. Neste estudo, construímos uma rede de interação entre doenças baseada na similaridade genética, para explorar a componente genética compartilhada entre a PEA e comorbilidades neurológicas e neuropsiquiátricas. As doenças analisadas incluem o Défice Intelectual (DI), a Perturbação de Hiperatividade/ Défice de Atenção (PHDA) e a Epilepsia, bem como outras doenças neuropsiquiátricas como a Esquizofrenia (SCZ) e a Perturbação Bipolar (PB). Usando a base de dados de doenças da DisGeNET, a similaridade genética entre as doenças analisadas foi calculada a partir do coeficiente de Jaccard entre pares de doenças, e o algoritmo de Leiden foi usado para identificar comunidades de doenças na rede. Identificámos uma comunidade heterogénea de doenças geneticamente mais semelhantes à PEA, que inclui a Epilepsia, a PB, a PHDA com apresentação combinada, e algumas perturbações no espetro da SCZ. Esta abordagem permitiu obter uma maior clarificação acerca da componente genética compartilhada entre a PEA e comorbilidades neurológicas e neuropsiquiátricas, com implicações importantes para a nosologia, fisiopatologia e o tratamento o personalizado da doença.
- Bridging Genetic Insights with Neuroimaging in Autism Spectrum Disorder - A Systematic ReviewPublication . Vilela, Joana; Rasga, Célia; Santos, João Xavier; Martiniano, Hugo; Marques, Ana Rita; Oliveira, Guiomar; Vicente, Astrid Moura; MDPIAutism Spectrum Disorder (ASD) is an early onset neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive patterns of behavior. Family studies show that ASD is highly heritable, and hundreds of genes have previously been implicated in the disorder; however, the etiology is still not fully clear. Brain imaging and electroencephalography (EEG) are key techniques that study alterations in brain structure and function. Combined with genetic analysis, these techniques have the potential to help in the clarification of the neurobiological mechanisms contributing to ASD and help in defining novel therapeutic targets. To further understand what is known today regarding the impact of genetic variants in the brain alterations observed in individuals with ASD, a systematic review was carried out using Pubmed and EBSCO databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review shows that specific genetic variants and altered patterns of gene expression in individuals with ASD may have an effect on brain circuits associated with face processing and social cognition, and contribute to excitation–inhibition imbalances and to anomalies in brain volumes.
- Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disordersPublication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João Xavier; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid MouraAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.
- Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disordersPublication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid MouraBackground/Objectives: Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder , with variable severity and multiple comorbidities. Given the previous evidence of genetic overlap between ASD and several comorbid brain disorders, we sought to explore the genetic similarity with ASD across a range of brain disorders, using a genetic similarity disease network approach. Methods: We developed a genetic similarity disease network between ASD and Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, Epilepsy, Schizophrenia and Bipolar Disease spectrum. Using gene-disease associations from the DisGeNET database, genetic similarities were estimated from the Jaccard coefficient between disease pairs. The Leiden algorithm identified network disease communities and shared biological pathways. Loss-of-function (LoF) rare de novo variants within shared genes underlying the disease communities were identified using the MSSNG whole-genome sequencing dataset. Results: We identified three disease communities. ASD is included in a heterogeneous community with Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. ASD and Intellectual Disability are in separate communities. The genes SHANK3, ASH1L, SCN2A, and CHD2, which are candidate genes for diseases in all communities, have a higher number of de novo rare LoF SNVs in ASD subjects. Conclusion: This approach enabled further clarification of genetic sharing between ASD and comorbid brain disorders, as we took advantage from a finer granularity in disease classification and multi-level evidence from DisGeNET, with important implications for disease nosology, pathophysiology, and personalized treatment.
- Estratégia Nacional para a Medicina Genómica (PT_MedGen)Publication . Vicente, Astrid MouraA Medicina Genómica utiliza a informação contida no DNA de cada individuo para informar os seus cuidados de saúde, contribuindo para diagnósticos mais precisos e atempados, para ajustar a terapêutica certa para cada individuo e para estimar a sua predisposiçao a determinadas doenças, potenciando a sua prevenção. É assim um componente-chave da Medicina Personalizada. (...)
- Estratégia Nacional para a Medicina Genómica - PT_MedGen: desafios e prioridadesPublication . Almeida, Fernando de; Vicente, Astrid Moura; Calado, Patrícia; Santos, Manuel; Carvalho, Ana Sofia; Águas, Cíntia; Pinto, Cátia Sousa; Silva, Mário Jorge Gaspar da; Melo, Ana Portugal; Oliveira, Mónica Duarte Correia de; Feijó, Joana; Vilarinho, Laura; Oliveira, CarlaO presente documento visa propor o conceito e as linhas de ação prioritárias da Estratégia Nacional para a Medicina Genómica (PT_MedGen). O documento baseia-se na auscultação de alguns dos principais stakeholders nacionais, representados na Comissão nomeada pelo Despacho n.o 5135/2021 coordenada pelo INSA, e ainda na consulta de outras entidades e peritos de relevância. A estratégia PT_MedGen tem a meta global de criar infraestruturas e processos que permitam a adoção de abordagens de medicina personalizada na prática clínica, a par com a contribuição para a iniciativa 1+MG. Esta estratégia promoverá ainda a investigação, a inovação, a competitividade e a internacionalização, permitindo a criação de conhecimento e valor significativos na área da saúde.
- Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum DisorderPublication . Marques, Ana Rita; Santos, João Xavier; Martiniano, Hugo; Vilela, Joana; Rasga, Célia; Romão, Luísa; Vicente, Astrid MouraAutism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA Decay (NMD) pathway, may contribute to ASD risk. In this study, we gathered a list of 46 NMD factors and regulators and investigated the role of genetic variants in these genes in ASD. By conducting a comprehensive search for Single Nucleotide Variants (SNVs) in NMD genes using Whole Exome Sequencing data from 1828 ASD patients, we identified 270 SNVs predicted to be damaging in 28.7% of the population. We also analyzed Copy Number Variants (CNVs) from two cohorts of ASD patients (N = 3570) and discovered 38 CNVs in 1% of cases. Importantly, we discovered 136 genetic variants (125 SNVs and 11 CNVs) in 258 ASD patients that were located within protein domains required for NMD. These gene variants are classified as damaging using in silico prediction tools, and therefore may interfere with proper NMD function in ASD. The discovery of NMD genes as candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.
- Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection AnalysisPublication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João Xavier; Asif, Muhammad; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid MouraAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein–protein interactions, and the etwork’s biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the PDE11A and SYTL3 genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.
- Neurometabolic profiles of autism spectrum disorder patients with genetic variants in specific neurotransmission and synaptic genesPublication . Vilela, Joana; Pereira, Andreia C.; Violante, Inês R.; Mouga, Susana; Rasga, Célia; Santos, João Xavier; Martiniano, Hugo; Marques, Ana Rita; Oliveira, Guiomar; Castelo-Branco, Miguel; Vicente, Astrid MouraAutism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction, and restricted and repetitive patterns of behavior. ASD presents as a clinical spectrum, with variable levels of severity and multiple co-occurring conditions. The etiology of ASD may involve hundreds of genes and there is evidence that neurotransmitter and synaptic (NS) pathways are implicated. Proton Magnetic Resonance Spectroscopy (H-MRS) has made it possible to study the concentration of brain neurometabolites and compare their levels in the brains of ASD and control individuals. We integrated genetic variants in NS genes with H-MRS analysis, and identified 12 predicted damaging variants (PDVs) in 12 NS genes in 10 ASD individuals, most mapping to genes involved in Gamma-aminobutyric acid (GABA) and glutamate pathways. Total creatine (tCr) and total N-acetyl aspartate (tNAA), markers of bioenergetics and neuronal metabolism, respectively, were lower in ASD patients with genetic alterations in NS genes compared to a control group without ASD. We conclude that PDVs in NS genes that are important for the regulation of glutamate or involved in GABAergic functions are associated with neurometabolic alterations, and that dysfunction in glutamatergic and/or GABAergic pathways may be implicated as these pathways are linked to the metabolic measures altered in cases.
- Perturbação do espectro do autismo: identificação de variantes em genes envolvidos no mecanismo regulador da expressão génica nonsense-mediated mRNA decayPublication . Marques, Ana Rita; Santos, João Xavier; Martiniano, Hugo; Vilela, Joana; Rasga, Célia; Romão, Luísa; Vicente, Astrid MouraA Perturbação do Espectro do Autismo (PEA) é uma patologia do neurodesenvolvimento caracterizada por dificuldades de socialização e/ou comunicação e por comportamentos estereotipados e repetitivos. Estudos de heritabilidade indicam que fatores genéticos contribuem para 50-80% do risco de desenvolver PEA, mas os mecanismos genéticos não são bem conhecidos. Neste estudo, exploramos a contribuição para o risco de PEA de genes que codificam proteínas envolvidas num mecanismo regulador da expressão génica, o Nonsense-Mediated mRNA Decay (NMD). Para este fim, compilámos uma lista de 46 genes envolvidos no NMD e investigámos a presença de Single Nucleotide Variants (SNVs) e Copy Number Variants (CNV ) nestes genes em duas amostras populacionais de indivíduos diagnosticados com PEA (n=1828 e n=3570, respetivamente). Identificámos variantes raras (MAF<1% em controlos) com efeito deletério de acordo com uma predição in silico, e verificámos se afetam domínios proteicos necessários para o NMD. Identificámos 270 SNVs em 524 pacientes com PEA e 38 CNVs em 38 pacientes com PEA. Destas, 136 variantes (122 SNVs e 11 CNVs) estão localizadas em regiões dos genes que codificam domínios proteicos importantes para o funcionamento do mecanismo de NMD. Deste modo, colocamos a hipótese de que estas variantes possam afetar a função normal do NMD e, consequentemente, contribuir para alterações na expressão dos genes-alvo, podendo assim constituir um fator de risco para a PEA.