Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction–associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.

中文翻译：

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对阿片类药物成瘾遗传学的新兴多组学理解


阿片类药物滥用、成瘾和相关的药物过量死亡仍然是全球公共卫生危机。尽管对药物治疗的需求巨大，但目前的选择在数量、用途和有效性方面受到限制。我们需要在对驱动阿片类药物成瘾的生物学的理解上取得根本性的飞跃，以指导开发更有效的药物辅助疗法。本综述侧重于组学鉴定的与阿片类药物成瘾相关的生物学特征。最近的 GWAS 已开始鉴定强大的遗传关联，包括 OPRM1、FURIN 和基因簇 SCAI/PPP6C/RABEPK 中的变异。越来越多的死后人脑组织的组学研究检查了不同大脑区域的生物学特征（例如，组蛋白修饰和基因表达），确定了与阿片类药物滥用者过量死亡相关的广泛基因失调。通过荟萃分析和多组学系统生物学汇总，并以模式生物研究为依据，富集阿片类药物成瘾相关基因的关键生物途径正在出现，其中包括与突触可塑性和神经元信号相关的信号通路（例如 Trk、ERK/MAPK、食欲素）相关的特异性受体（例如 GABAB 受体、GPCR 和 Trk）。利用组学不可知论的发现能力并将其置于功能神经生物学的背景下的研究将推动我们取得急需的、改变领域的突破，包括确定治疗这种毁灭性脑部疾病的药物开发的可操作靶点。