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Open Access 01-12-2019 | Research

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation

Authors: Ayden Saffari, Matt Arno, Eric Nasser, Angelica Ronald, Chloe C. Y. Wong, Leonard C. Schalkwyk, Jonathan Mill, Frank Dudbridge, Emma L. Meaburn

Published in: Molecular Autism | Issue 1/2019

Abstract

Background

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.

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Title: RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation
Authors: Ayden Saffari
Matt Arno
Eric Nasser
Angelica Ronald
Chloe C. Y. Wong
Leonard C. Schalkwyk
Jonathan Mill
Frank Dudbridge
Emma L. Meaburn
Publication date: 01-12-2019
Publisher: BioMed Central
Published in: Molecular Autism / Issue 1/2019
Electronic ISSN: 2040-2392
DOI: https://doi.org/10.1186/s13229-019-0285-1

2024 ASCO Annual Meeting

Springer Medicine

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation

Abstract

Background

Methods

Results

Limitations

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Limitations

Conclusions

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