Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.

中文翻译：

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对自杀完成者大脑皮层影响分子性状的遗传变异的探索性分析。

遗传因素与自杀行为有关。已经提出遗传因素在自杀中的作用之一可以由遗传变异对基因表达调控的影响来表示。已经证明了自杀性脑中参与多个生物系统的基因表达的改变，因此必须确定可能影响基因表达或其调控机制的遗传变异。在这项研究中，我们整合了自杀前额叶皮层的DNA甲基化，基因表达和基因型数据，以鉴定可能是基因表达调控因素的遗传变异，通常称为定量性状基因座（xQTL）。我们确定了6,224个甲基化定量性状基因座和2个 自杀完成者前额叶皮层中的239个表达数量性状基因座（eQTL）。鉴定出的xQTL影响神经发育和细胞组织相关基因的表达。之前鉴定出的两个eQTL（rs8065311和rs1019238）与大麻依赖相关，突显了一种物质滥用障碍患者自杀风险增加的候选遗传变异。我们的发现表明，遗传变异可能通过调节启动子和增强子的活性，并在较小程度上结合转录因子来调节自杀前额叶皮层中的基因表达。之前鉴定出的两个eQTL（rs8065311和rs1019238）与大麻依赖相关，突显了一种物质滥用障碍患者自杀风险增加的候选遗传变异。我们的发现表明，遗传变异可能通过调节启动子和增强子的活性，并在较小程度上结合转录因子来调节自杀前额叶皮层中的基因表达。之前鉴定出的两个eQTL（rs8065311和rs1019238）与大麻依赖相关，突显了一种物质滥用障碍患者自杀风险增加的候选遗传变异。我们的发现表明，遗传变异可能通过调节启动子和增强子的活性，并在较小程度上结合转录因子来调节自杀前额叶皮层中的基因表达。