Suicide is the second leading cause of death in U.S. adolescents and young adults and is generally associated with a psychiatric disorder. Suicidal behavior has a complex etiology and pathogenesis. Moderate heritability suggests genetic causes. Associations between childhood and recent life adversity indicate contributions from epigenetic factors. Genomic contributions to suicide pathogenesis remain largely unknown. This article is based on a workshop held to design strategies to identify molecular drivers of suicide neurobiology that would be putative new treatment targets. The panel determined that while bulk tissue studies provide comprehensive information, single-nucleus approaches that identify cell type–specific changes are needed. While single-nuclei techniques lack information on cytoplasm, processes, spines, and synapses, spatial multiomic technologies on intact tissue detect cell alterations specific to brain tissue layers and subregions. Because suicide has genetic and environmental drivers, multiomic approaches that combine cell type–specific epigenome, transcriptome, and proteome provide a more complete picture of pathogenesis. To determine the direction of effect of suicide risk gene variants on RNA and protein expression and how these interact with epigenetic marks, single-nuclei and spatial multiomics quantitative trait loci maps should be integrated with whole-genome sequencing and genome-wide association databases. The workshop concluded with a recommendation for the formation of an international suicide biology consortium that will bring together brain banks and investigators with expertise in cutting-edge omics technologies to delineate the biology of suicide and identify novel potential treatment targets to be tested in cellular and animal models for drug and biomarker discovery to guide suicide prevention.

中文翻译：

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研究自杀发病机制的组学方法


自杀是美国青少年和年轻人的第二大死因，通常与精神疾病有关。自杀行为具有复杂的病因和发病机制。中度遗传性提示遗传原因。童年和近期生活逆境之间的关联表明表观遗传因素的贡献。基因组对自杀发病机制的贡献在很大程度上仍然未知。本文基于一个研讨会，该研讨会旨在设计策略以确定自杀神经生物学的分子驱动因素，这些驱动因素将成为假定的新治疗目标。该小组确定，虽然大量组织研究提供了全面的信息，但需要识别细胞类型特异性变化的单核方法。虽然单核技术缺乏有关细胞质、过程、脊柱和突触的信息，但完整组织的空间多组学技术可检测特定于脑组织层和亚区域的细胞改变。由于自杀具有遗传和环境驱动因素，因此结合细胞类型特异性表观基因组、转录组和蛋白质组的多组学方法提供了更完整的发病机制图。为了确定自杀风险基因变异对 RNA 和蛋白质表达的影响方向以及它们如何与表观遗传标记相互作用，应将单核和空间多组学数量性状位点图与全基因组测序和全基因组关联数据库相结合。 研讨会结束时建议成立一个国际自杀生物学联盟，该联盟将汇集脑库和具有尖端组学技术专业知识的研究人员，以描述自杀的生物学特征，并确定新的潜在治疗靶点，以便在细胞和动物模型中进行测试，以发现药物和生物标志物，以指导自杀预防。