Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina, USA.
Autism Res. 2023 Mar;16(3):502-523. doi: 10.1002/aur.2884. Epub 2023 Jan 7.
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 SUMMARY: Oxytocin (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.
催产素（OT）是大脑中含量最丰富的神经肽，在社交显著性和动机方面发挥着重要作用。OT 在自闭症谱系障碍（ASD）中的疗效的临床试验报告结果喜忧参半，部分原因是 ASD 的复杂病因。我们研究了遗传和表观遗传变异是否会导致内源性 OT 水平的变化，从而影响 OT 治疗的敏感性。为了进行这项分析，我们整合了 290 名 ASD 参与者的全基因组 DNA 甲基化、转录活性和遗传变异与 OT 治疗血浆 OT 水平的图谱，这些参与者参与了一项 OT 的随机对照试验。我们的分析确定了与血浆 OT 具有新关联的遗传变异，其中一些位于已知的 ASD 风险基因中。我们还显示了血浆 OT 水平与几个注释基因集的外周转录活性和 DNA 甲基化图谱之间存在微妙但具有统计学意义的关联。这些发现拓宽了我们对周围 OT 系统的影响的理解，并为未来的研究提供了新的遗传候选基因，以解码 ASD 的复杂病因及其与 OT 信号和基于 OT 的干预的相互作用。
简而言之：OT 是神经元产生的一种丰富的化学物质，在社交互动和动机中起着重要作用。我们研究了遗传和表观遗传因素是否会导致血液中 OT 水平的变化。为此，我们将自闭症患者的遗传、基因表达和非 DNA 调节（表观遗传）特征与 OT 临床试验中的 290 名患者的血液 OT 水平进行了整合。我们确定了与血浆 OT 相关的遗传关联，其中一些位于已知的自闭症风险基因中。我们还显示了血浆 OT 水平与几个基因途径的基因表达和表观遗传之间具有统计学意义的关联。这些发现拓宽了我们对影响血液中 OT 水平的因素的理解，为未来的研究提供了解码自闭症的复杂表现及其与 OT 和基于 OT 的治疗相互作用的新线索。
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