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.

中文翻译：

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自闭症不一致的同卵双胞胎的RNA测序揭示了基于血液的特征，涉及免疫和转录失调。

背景技术在我们对遗传和环境风险因素如何在分子水平上趋同以导致自闭症症状出现的机制理解上，存在一个空白。我们比较了自闭症谱系条件（ASC）一致和不一致的同卵双胞胎中基于血液的基因表达特征，以区分遗传和环境驱动的转录差异，并建立了涉及ASC的生物学机制的聚集证据。方法使用RNA-seq从16对单卵双胞胎（MZ）双胞胎和7对双胞胎双胞胎成员（总共39名个体）采集的全血样本中获得全基因组全基因表达数据，这些成员已在年龄进行了ASC和自闭症特征评估12 在（a）受影响和未受影响的受试者（N = 36）与（b）不一致的ASC MZ双胞胎对（总共N = 11）之间进行差异表达（DE）分析，以鉴定环境驱动的DE。在DE基因清单上进行基因集富集和途径测试。最后，使用DNA甲基化数据进行的综合分析旨在鉴定具有一致证据证明顺式调控发生变化的基因。结果在不一致双胞胎分析中，三个基因显示了FDR <10％时DE的证据：IGHG4，EVI2A和SNORD15B。在病例对照分析中，在FDR <10％时鉴定出四个DE基因，包括IGHG4，PRR13P5，DEPDC1B和ZNF501。我们在SFARI人类基因数据库中找到了丰富的DE基因。显示富集证据的途径包括与免疫细胞信号转导和免疫反应有关的途径，转录控制和细胞周期/增殖。综合的基因组和转录组分析确定了许多基因，这些基因显示出顺式失调的暗示证据。局限性很少有与ASC稳定不一致的同卵双胞胎，因此样本量有限，并且仅限于使用外周血组织进行转录和甲基化谱分析。鉴于这些主要限制，我们专注于笔录级别的分析。结论使用一组ASC不协调和一致的MZ双胞胎，我们为ASC分子病因学中基于免疫的成分的转录组学证据的增加，增加了人体的数量。虽然样本数量有限，