Neuropsychiatric disorders are highly heritable polygenic disorders arising from the complex interplay of highly penetrant rare variants and common variants of small effect. There is a large index of comorbidity and shared genetic risk between disorders, reflecting the pleiotropy of individual variants as well as predicted downstream pathway-level convergence. Importantly, the mechanism(s) through which psychiatric disease-associated variants interact to contribute to disease risk remains unknown. Human induced pluripotent stem cell (hiPSC)-based models are increasingly useful for the systematic study of the complex genetics associated with brain diseases, particularly when combined with CRISPR-mediated genomic engineering, which together facilitate isogenic comparisons of defined neuronal cell types. In this review, we discuss the latest CRISPR technologies and consider how they can be successfully applied to the functional characterization of the growing list genetic variants linked to psychiatric disease.

神经精神疾病是高度遗传的多基因疾病，由高度渗透的罕见变异和小影响的常见变异的复杂相互作用引起。疾病之间存在大量共病和共同遗传风险，反映了个体变异的多效性以及预测的下游途径水平的收敛。重要的是，精神疾病相关变异相互作用导致疾病风险的机制仍然未知。基于人类诱导多能干细胞 (hiPSC) 的模型对于系统研究与脑部疾病相关的复杂遗传学越来越有用，特别是与 CRISPR 介导的基因组工程相结合时，它们共同促进了定义的神经元细胞类型的同基因比较。在这篇综述中，我们讨论了最新的 CRISPR 技术，并考虑如何将它们成功应用于与精神疾病相关的不断增长的遗传变异的功能表征。