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dc.contributor.authorMill, Jonathan
dc.date.accessioned2020-11-16T15:08:05Z
dc.date.available2020-11-16T15:08:05Z
dc.date.issued2019-11-07
dc.identifier.citationSaffari A et al. RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation. Mol Autism. 2019 Nov 7;10:38.en_US
dc.identifier.pmid31719968
dc.identifier.doi10.1186/s13229-019-0285-1
dc.identifier.urihttps://rde.dspace-express.com/handle/11287/621548
dc.description.abstractBackground: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals.en_US
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.relation.urlhttps://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0285-1en_US
dc.rights© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
dc.rightsCC0 1.0 Universal*
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/*
dc.subjectAutism spectrum disorderen_US
dc.subjectDNA methylationen_US
dc.subjectDiscordanceen_US
dc.subjectEpigenomicsen_US
dc.subjectGene expressionen_US
dc.subjectImmuneen_US
dc.subjectMZ twinsen_US
dc.subjectRNA-seqen_US
dc.subjectTranscriptomicsen_US
dc.titleRNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulationen_US
dc.typeJournal Articleen_US
dc.identifier.journalMolecular Autismen_US
dc.identifier.pmcidPMC6839145
dc.description.noteThis article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.en_US
dc.description.fundingWe gratefully acknowledge the ongoing contribution of the participants in the Twins Early Development Study (TEDS) and their families. TEDS is supported by a program grant to RP from the UK Medical Research Council [MR/M021475/1 and previously G0901245]. The study was funded by a research grant from the Royal Society awarded to ELM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_US
dc.type.versionPublisheden_US
dc.description.admin-notepublished version, accepted versionen_US


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© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Except where otherwise noted, this item's license is described as © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.