The interaction between genes and environment often occurs when they depend on one another. We hypothesized that adverse childhood experiences (ACEs) would interact with genetic predispositions to bipolar disorder (BD), demonstrating earlier age at onset (AAO) and worse clinical outcomes. We aimed to clarify the effects of the interaction between ACEs and genetic susceptibility using polygenic risk score (PRS) on AAO and clinical outcomes. Single nucleotide polymorphisms and clinical data, including ACEs, were obtained from the Bipolar Genomic Study, which contains a large sample of BD participants. A total of 1615 subjects with BD I were obtained and divided into two groups according to the presence or absence of ACEs and an additional four groups based on the number of ACEs (none versus one versus two versus ≥ three types). ACEs was evaluated using the childhood life events scale (CLES). BD–PRS was obtained from the Psychiatric Genomics Consortium, which compared BD patients and healthy controls. The BD–PRS was higher in the group with ACEs than without ACEs at most p-value thresholds. In multivariate linear regression analyses, both groups with more ACEs and higher BD–PRS were independently and interactively associated with an earlier AAO of BD; however, only greater ACEs were associated with worsened clinical outcome. These findings highlight the clinical importance of evaluating ACEs and polygenic risk in research of the etiology of BD.

基因和环境之间的相互作用经常发生在它们相互依赖时。我们假设不良的童年经历 (ACE) 会与双相情感障碍 (BD) 的遗传易感性相互作用，表现出较早的发病年龄 (AAO) 和更差的临床结果。我们旨在使用多基因风险评分 (PRS) 阐明 ACE 与遗传易感性之间的相互作用对 AAO 和临床结果的影响。单核苷酸多态性和临床数据（包括 ACE）来自双极基因组研究，其中包含大量 BD 参与者样本。总共获得了 1615 名患有 BD I 的受试者，并根据 ACE 的存在或不存在分为两组，并根据 ACE 的数量再分为四组（无对 1 对 2 对≥三种类型）。ACE 使用儿童生活事件量表 (CLES) 进行评估。BD-PRS 来自精神病基因组学联盟，该联盟将 BD 患者和健康对照进行了比较。有ACEs组的BD-PRS最多高于没有ACEs的组p值阈值。在多元线性回归分析中，具有更多 ACE 和更高 BD-PRS 的两组均与早期 BD 的 AAO 独立且交互相关；然而，只有更大的 ACE 与恶化的临床结果相关。这些发现强调了评估 ACE 和多基因风险在 BD 病因研究中的临床重要性。