Objective:

The authors sought to study the transcriptomic and genomic features of completed suicide by parsing the method chosen, to capture molecular correlates of the distinctive frame of mind of individuals who die by suicide, while reducing heterogeneity.

Methods:

The authors analyzed gene expression (RNA sequencing) from postmortem dorsolateral prefrontal cortex of patients who died by suicide with violent compared with nonviolent means, nonsuicide patients with the same psychiatric disorders, and a neurotypical group (total N=329). They then examined genomic risk scores (GRSs) for each psychiatric disorder included, and GRSs for cognition (IQ) and for suicide attempt, testing how they predict diagnosis or traits (total N=888).

Results:

Patients who died by suicide by violent means showed a transcriptomic pattern remarkably divergent from each of the other patient groups but less from the neurotypical group; consistently, their genomic profile of risk was relatively low for their diagnosed illness as well as for suicide attempt, and relatively high for IQ: they were more similar to the neurotypical group than to other patients. Differentially expressed genes (DEGs) associated with patients who died by suicide by violent means pointed to purinergic signaling in microglia, showing similarities to a genome-wide association study of Drosophila aggression. Weighted gene coexpression network analysis revealed that these DEGs were coexpressed in a context of mitochondrial metabolic activation unique to suicide by violent means.

Conclusions:

These findings suggest that patients who die by suicide by violent means are in part biologically separable from other patients with the same diagnoses, and their behavioral outcome may be less dependent on genetic risk for conventional psychiatric disorders and be associated with an alteration of purinergic signaling and mitochondrial metabolism.

中文翻译：

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自杀的遗传学和脑转录组学

 客观的：

作者试图通过解析所选方法来研究自杀完成的转录组和基因组特征，以捕获自杀者独特心态的分子相关性，同时减少异质性。

 方法：

作者分析了暴力自杀患者与非暴力自杀患者、患有相同精神疾病的非自杀患者以及神经典型组（总计 N=329）的死后背外侧前额叶皮层的基因表达（RNA 测序）。然后，他们检查了每种精神疾病的基因组风险评分 (GRS)，以及认知 (IQ) 和自杀企图的 GRS，测试它们如何预测诊断或特征（总计 N=888）。

 结果：

通过暴力手段自杀的患者表现出与其他患者组显着不同的转录组模式，但与神经典型组的差异较小；一致地，他们的诊断疾病和自杀企图的基因组风险相对较低，而智商则相对较高：与其他患者相比，他们与神经典型组更相似。与暴力自杀患者相关的差异表达基因（DEG）指向小胶质细胞中的嘌呤能信号，显示出与果蝇攻击性的全基因组关联研究的相似性。加权基因共表达网络分析表明，这些差异表达基因是在暴力自杀所特有的线粒体代谢激活背景下共表达的。

 结论：

这些发现表明，通过暴力手段自杀的患者在生物学上与其他具有相同诊断的患者是部分分离的，他们的行为结果可能较少依赖于传统精神疾病的遗传风险，并与嘌呤能信号的改变和线粒体代谢。