Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

中文翻译：

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高多基因负担与有自杀行为的个体的血液 DNA 甲基化变化有关。

自杀行为是多种因素相互作用的结果，包括遗传和环境因素。考虑自杀行为的多基因成分的方法的整合，例如多基因风险评分 (PRS) 和 DNA 甲基化，有望提高我们对这种行为中遗传和环境因素之间复杂相互作用的理解。本研究的目的是评估具有高和低自杀遗传负担的个体之间的 DNA 甲基化差异。本研究分为两个阶段。在第一阶段，使用 Psycharray 芯片对 568 名墨西哥人的发现样本进行基因分型，其中 149 人有自杀行为（64 人有自杀念头，50 人有自杀企图，35 人完成自杀）。然后，在发现样本中进行了基于来自精神病学基因组联盟的汇总统计数据的 PRS 分析。在第二阶段，我们在 94 名受试者的发现样本（目标样本）的子样本中评估了具有高和低遗传负担的个体之间的 DNA 甲基化差异。我们确定了低和高 PRS 个体之间的 153 个差异甲基化位点。在映射到差异甲基化位点的基因中，我们发现了参与神经发育（CHD7、RFX4、KCNA1、PLCB1、PITX1、NUMBL）和 ATP 结合（KIF7、NUBP2、KIF6、ATP8B1、ATP11A、CLCN7、MYLK、MAP2K5）的基因。我们的研究结果表明，遗传变异可能会增加参与神经发育的基因表观遗传变异的倾向。