Regulatory RNAs in Autism Spectrum Disorder - modulation of genomic variant effects on clinical phenotype and brain structure and function

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Role of neurotransmission and synaptic processes in Autism Spectrum Disorder

Publication . Vilela, Joana; Vicente, Astrid Moura; Oliveira, Guiomar

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and interaction and repetitive, restricted behaviors. Individuals with ASD may present a variety of clinical and behavioral symptoms, as well as a number of comorbidities, leading to variable degrees of clinical severity. ASD segregate in families and genetics has a significant contribution to the disease’s development. In this PhD thesis, we focused on exploring the role of neurotransmitter and synaptic genes (NS genes) in ASD. Going beyond the identification of ASD risk genes, the main objective was to clarify the biological processes affected by gene variants in NS genes in ASD and the global networks that link those processes together, using a systems medicine approach. A genetic similarity disease network approach was developed to explore the shared genetics between ASD and comorbid brain diseases. A Knowledge Graph was developed to take advantage of novel gene-disease predictions for disease terms related to ASD to identify and characterize biological pathways implicated in the disorder. In this thesis, it was also performed a community detection analysis using protein–protein interactions involved in ASD, defined by variants in NS genes found in large exomic datasets of ASD subjects. A literature review was also carried out, targeting studies that integrate data related with genetic alterations and their implications in changes in brain structure and function, in individuals with ASD. This PhD thesis also showed that brain imaging data obtained through magnetic resonance and electroencephalography, combined with genetic analysis, has the potential to help in the understanding of the neurobiological mechanisms that contribute to the development of ASD, and in the definition of new therapeutic targets. Finally, the contribution of synaptic dysregulation to ASD was investigated integrating measures of brain metabolites obtained through proton magnetic resonance spectroscopy (1H-MRS) with data on genetic variation.

2024-12-02Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

PD/BD/131390/2017