Department of Psychiatry, Department of Genetics, Wu Tsai Institute at Yale, and Yale Stem Cell Center, Yale University School of Medicine, New Haven, Conn.
Am J Psychiatry. 2022 May;179(5):322-328. doi: 10.1176/appi.ajp.20220235.
There is an urgent and unmet need to advance our ability to translate genetic studies of psychiatric disorders into clinically actionable information, which could transform diagnostics and even one day lead to novel (and potentially presymptomatic) therapeutic interventions. Today, although there are hundreds of significant loci associated with psychiatric disorders, resolving the target gene(s) and pathway(s) impacted by each is a major challenge. Integrating human induced pluripotent stem cell-based approaches with CRISPR-mediated genomic engineering strategies makes it possible to study the impact of patient-specific variants within the cell types of the brain. As the scale and scope of functional genomic studies expands, so does our ability to resolve the complex interplay of the many risk variants linked to psychiatric disorders. In this review, the author discusses some of the technological advances that make it possible to ask exciting questions that are fundamental to our understanding of psychiatric disorders. How do distinct risk variants converge and interact with each other (and the environment) across the diverse cell types that comprise the human brain? Can clinical trajectories and/or therapeutic response be predicted from genetic profiles? Just as critically, by spreading the message that genetic risk for psychiatric disorders is biological and fundamentally no different than for other human conditions, we can dispel the stigma associated with mental illness.
目前，迫切需要提高我们将精神疾病遗传学研究转化为临床实用信息的能力，这可能会改变诊断方法，甚至有朝一日会带来新的（甚至是有症状前的）治疗干预手段。虽然目前已经发现了数百个与精神疾病相关的重要基因座，但确定每个基因座所影响的靶基因和途径仍然是一个重大挑战。将基于人类诱导多能干细胞的方法与 CRISPR 介导的基因组工程策略相结合，使得研究特定于患者的变异在大脑细胞类型中的影响成为可能。随着功能基因组研究规模和范围的扩大，我们也越来越有能力解析与精神疾病相关的众多风险变异之间复杂的相互作用。在这篇综述中，作者讨论了一些使我们能够提出一些关于精神疾病理解的基本问题的技术进步。不同的风险变异如何在构成人类大脑的不同细胞类型中相互汇聚和相互作用（以及与环境相互作用）？是否可以根据遗传特征预测临床病程和/或治疗反应？同样重要的是，通过传播精神疾病的遗传风险是生物学的，并且与其他人类疾病没有本质区别的信息，我们可以消除与精神疾病相关的污名。
