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Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis
Autism 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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668950/ https://www.ncbi.nlm.nih.gov/pubmed/38001974 http://dx.doi.org/10.3390/biomedicines11112971 |
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author | Vilela, Joana Martiniano, Hugo Marques, Ana Rita Santos, João Xavier Asif, Muhammad Rasga, Célia Oliveira, Guiomar Vicente, Astrid Moura |
author_facet | Vilela, Joana Martiniano, Hugo Marques, Ana Rita Santos, João Xavier Asif, Muhammad Rasga, Célia Oliveira, Guiomar Vicente, Astrid Moura |
author_sort | Vilela, Joana |
collection | PubMed |
description | Autism 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 network’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. |
format | Online Article Text |
id | pubmed-10668950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106689502023-11-04 Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis Vilela, Joana Martiniano, Hugo Marques, Ana Rita Santos, João Xavier Asif, Muhammad Rasga, Célia Oliveira, Guiomar Vicente, Astrid Moura Biomedicines Article Autism 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 network’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. MDPI 2023-11-04 /pmc/articles/PMC10668950/ /pubmed/38001974 http://dx.doi.org/10.3390/biomedicines11112971 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Vilela, Joana Martiniano, Hugo Marques, Ana Rita Santos, João Xavier Asif, Muhammad Rasga, Célia Oliveira, Guiomar Vicente, Astrid Moura Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
title | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
title_full | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
title_fullStr | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
title_full_unstemmed | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
title_short | Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis |
title_sort | identification of neurotransmission and synaptic biological processes disrupted in autism spectrum disorder using interaction networks and community detection analysis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668950/ https://www.ncbi.nlm.nih.gov/pubmed/38001974 http://dx.doi.org/10.3390/biomedicines11112971 |
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