Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder
Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder
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DOI：
10.1002/aur.2884
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发表时间：
2023-01-07
期刊：
影响因子：
4.7
通讯作者：
Gregory，Simon G.
中科院分区：
文献类型：
--
作者：
Siecinski，Stephen K.;Giamberardino，Stephanie N.;Gregory，Simon G.
催产素（OT）是大脑中含量最丰富的神经肽，在社会意识和动机中起着重要作用。OT在自闭症谱系障碍（ASD）中的疗效的临床试验报告了部分由于ASD的复杂病因导致的混合结果。我们研究了遗传和表观遗传变异是否有助于调节OT治疗敏感性的可变内源性OT水平。为了进行这项分析，我们整合了290名参加OT随机对照试验的ASD参与者的DNA甲基化，转录活性和遗传变异的全基因组谱与血浆OT水平。我们的分析确定了与血浆OT具有新关联的遗传变异，其中一些存在于已知的ASD风险基因中。我们还显示了血浆OT水平与外周转录活性和几个注释基因集的DNA甲基化谱之间的微妙但统计学显著的相关性。这些发现拓宽了我们对外周催产素系统影响的理解，并为未来的研究提供了新的遗传候选者，以解码ASD的复杂病因及其与OT信号和基于OT的干预措施的相互作用。Lay SummaryOxytocin（OT）是一种由神经元产生的丰富化学物质，在社会互动和动机中发挥重要作用。我们调查了遗传和表观遗传因素是否有助于血液中的可变OT水平。为此，我们在参加OT临床试验的290名自闭症参与者中将遗传、基因表达和非DNA调节（表观遗传）特征与血液OT水平进行了整合。我们确定了与血浆OT的遗传关联，其中一些存在于已知的自闭症风险基因中。我们还显示了血浆OT水平与几种基因途径的基因表达和表观遗传的统计学显著相关性。这些发现拓宽了我们对影响血液中OT水平的因素的理解，以便未来的研究解码自闭症的复杂表现及其与OT和OT治疗的相互作用。
Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome‐wide profiles of DNA‐methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA‐methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT‐based interventions.Lay SummaryOxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non‐DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT‐based treatment.