Neuroscience Research Australia, Sydney, NSW, Australia.
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Transl Psychiatry. 2022 Aug 3;12(1):310. doi: 10.1038/s41398-022-02079-6.
Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS; n = 41) compared against the bottom two quintiles (Low-BD-PRS; n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603; p = 3.54 × 10) in VARS2, a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs (p < 0.05); these displayed convergence with genes previously associated with BD, schizophrenia, chronotype, and risk taking. We tested poly-methylomic epigenetic profiles derived from nominal DMPs in two independent samples (n = 54 and n = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration.
环境因素会导致双相情感障碍（BD）的发病风险，但在遗传风险升高的情况下，环境因素如何影响精神病理学的发展尚不清楚。本研究旨在鉴定在具有 BD 家族高风险（HR）的年轻人中，与 BD 多基因风险相关的表观遗传特征。使用 Illumina PsychArray 检测外周血衍生的 DNA，并使用 Methylation-450K 或 -EPIC BeadChips 进行检测。使用最近全基因组关联研究的汇总统计数据计算多基因风险评分（PRS），这些研究涉及 BD、重度抑郁症（MDD）和跨疾病（八种精神疾病的荟萃分析）。根据其在 HR 人群分布中的 BD-PRS 评分，对欧洲血统的 HR 参与者（n=103）进行分层，然后将前两个五分位数（高 BD-PRS；n=41）与后两个五分位数（低 BD-PRS；n=41）进行比较。高 BD-PRS 组的平均跨疾病 PRS 和 MDD-PRS 更高（ANCOVA p=0.035 和 p=0.024）。我们使用线性模型评估高 BD-PRS 和低 BD-PRS 组之间的 DNA 甲基化差异。在线粒体氨酰-tRNA 合成酶 VARS2 中，一个差异甲基化探针（cg00933603；p=3.54×10）在经过多次检验校正后仍显著呈低甲基化状态。总体而言，BD-PRS 似乎广泛影响表观遗传过程，有 1183 个基因映射到名义 DMP（p<0.05）；这些基因与之前与 BD、精神分裂症、昼夜节律和冒险行为相关的基因存在收敛性。我们在两个独立样本（n=54 和 n=82）中测试了来自名义 DMP 的多甲基化表观遗传谱，并对家庭环境的影响进行了探索性评估，该环境指数反映了凝聚力和灵活性。本研究强调了遗传风险和表观遗传因素之间的重要相互作用，值得进一步探索。
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