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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\u2013protein interactions, and the network\u2019s 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.<\/jats:p>","DOI":"10.3390\/biomedicines11112971","type":"journal-article","created":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T14:51:01Z","timestamp":1699109461000},"page":"2971","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis"],"prefix":"10.3390","volume":"11","author":[{"given":"Joana","family":"Vilela","sequence":"first","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-8913","authenticated-orcid":false,"given":"Hugo","family":"Martiniano","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4144-7020","authenticated-orcid":false,"given":"Ana Rita","family":"Marques","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2797-5513","authenticated-orcid":false,"given":"Jo\u00e3o Xavier","family":"Santos","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"}]},{"given":"Muhammad","family":"Asif","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"},{"name":"Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad 38000, Pakistan"}]},{"given":"C\u00e9lia","family":"Rasga","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"}]},{"given":"Guiomar","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Unidade de Neurodesenvolvimento e Autismo, Servi\u00e7o do Centro de Desenvolvimento da Crian\u00e7a, Centro de Investiga\u00e7\u00e3o e Forma\u00e7\u00e3o Cl\u00ednica, Hospital Pedi\u00e1trico, Centro Hospitalar e Universit\u00e1rio de Coimbra (CHUC), 3000-602 Coimbra, Portugal"},{"name":"Coimbra Institute for Biomedical Imaging and Translational Research, University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, 3000-602 Coimbra, Portugal"}]},{"given":"Astrid Moura","family":"Vicente","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,4]]},"reference":[{"key":"ref_1","unstructured":"(2013). 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