A major genetic risk factor for psychosis is 22q11.2 deletion (22q11.2DS). However, robust and replicable functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis remain elusive due to small sample sizes and a focus on small single-site cohorts. Here, we identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis, and their links with idiopathic early psychosis, using one of the largest multi-cohort data to date. We obtained multi-cohort clinical phenotypic and task-free fMRI data from 856 participants (101 22q11.2DS, 120 idiopathic early psychosis, 101 idiopathic autism, 123 idiopathic ADHD, and 411 healthy controls) in a case-control design. A novel spatiotemporal deep neural network (stDNN)-based analysis was applied to the multi-cohort data to identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis. Next, stDNN was used to test the hypothesis that the functional brain signatures of 22q11.2DS-associated psychosis overlap with idiopathic early psychosis but not with autism and ADHD. stDNN-derived brain signatures distinguished 22q11.2DS from controls, and 22q11.2DS-associated psychosis with very high accuracies (86–94%) in the primary cohort and two fully independent cohorts without additional training. Robust distinguishing features of 22q11.2DS-associated psychosis emerged in the anterior insula node of the salience network and the striatum node of the dopaminergic reward pathway. These features also distinguished individuals with idiopathic early psychosis from controls, but not idiopathic autism or ADHD. Our results reveal that individuals with 22q11.2DS exhibit a highly distinct functional brain organization compared to controls. Additionally, the brain signatures of 22q11.2DS-associated psychosis overlap with those of idiopathic early psychosis in the salience network and dopaminergic reward pathway, providing substantial empirical support for the theoretical aberrant salience-based model of psychosis. Collectively, our findings, replicated across multiple independent cohorts, advance the understanding of 22q11.2DS and associated psychosis, underscoring the value of 22q11.2DS as a genetic model for probing the neurobiological underpinnings of psychosis and its progression.

精神病的一个主要遗传风险因素是 22q11.2 缺失 (22q11.2DS)。然而，由于样本量较小且关注小型单位点队列，22q11.2DS 和 22q11.2DS 相关精神病的稳健且可复制的功能性大脑特征仍然难以捉摸。在这里，我们使用迄今为止最大的多队列数据之一，确定了 22q11.2DS 和 22q11.2DS 相关精神病的功能性大脑特征，以及它们与特发性早期精神病的联系。我们通过病例对照设计获得了 856 名参与者（101 名 22q11.2DS、120 名特发性早期精神病、101 名特发性自闭症、123 名特发性 ADHD 和 411 名健康对照）的多队列临床表型和无任务 fMRI 数据。基于新型时空深度神经网络 (stDNN) 的分析应用于多队列数据，以识别 22q11.2DS 和 22q11.2DS 相关精神病的功能性大脑特征。接下来，stDNN 用于检验以下假设：22q11.2DS 相关精神病的功能性大脑特征与特发性早期精神病重叠，但与自闭症和 ADHD 不重叠。 stDNN 衍生的大脑特征在主要队列和两个完全独立的队列（无需额外训练）中以非常高的准确度（86-94%）区分 22q11.2DS 与对照以及 22q11.2DS 相关精神病。 22q11.2DS 相关精神病的显着特征出现在显着网络的前岛叶节点和多巴胺能奖赏通路的纹状体节点中。这些特征也可以将特发性早期精神病患者与对照组区分开来，但不能将特发性自闭症或多动症患者区分开来。我们的结果表明，与对照组相比，具有 22q11.2DS 的个体表现出高度独特的功能性大脑组织。此外，22q11.2DS相关精神病的大脑特征与特发性早期精神病在显着性网络和多巴胺能奖励通路中的大脑特征重叠，为基于异常显着性的精神病理论模型提供了实质性的经验支持。总的来说，我们的研究结果在多个独立队列中得到重复，促进了对 22q11.2DS 和相关精神病的理解，强调了 22q11.2DS 作为探索精神病及其进展的神经生物学基础的遗传模型的价值。