Genetic risk variants and transcriptional expression changes in autism spectrum disorder (ASD) were widely investigated, but their causal relationship remains largely unknown. Circular RNAs (circRNAs) are abundant in brain and often serve as upstream regulators of mRNAs. By integrating RNA-sequencing with genotype data from autistic brains, we assessed expression quantitative trait loci of circRNAs (circQTLs) that cis-regulated expression of nearby circRNAs and trans-regulated expression of distant genes (trans-eGenes) simultaneously. We thus identified 3619 circQTLs that were also trans-eQTLs and constructed 19,804 circQTL-circRNA-trans-eGene regulatory axes. We conducted two different types of approaches, mediation and partial correlation tests (MPT), to determine the axes with mediation effects of circQTLs on trans-eGene expression through circRNA expression. We showed that the mediation effects of the circQTLs (trans-eQTLs) on circRNA expression were positively correlated with the magnitude of circRNA-trans-eGene correlation of expression profile. The positive correlation became more significant after adjustment for the circQTLs. Of the 19,804 axes, 8103 passed MPT. Meanwhile, we performed causal inference test (CIT) and identified 2070 circQTL-trans-eGene-ASD diagnosis propagation paths. We showed that the CIT-passing genes were significantly enriched for ASD risk genes, genes encoding postsynaptic density proteins, and other ASD-relevant genes, supporting the relevance of the CIT-passing genes to ASD pathophysiology. Integration of MPT- and CIT-passing axes further constructed 352 circQTL-circRNA-trans-eGene-ASD diagnosis propagation paths, wherein the circRNA-trans-eGene axes may act as causal mediators for the circQTL-ASD diagnosis associations. These analyses were also successfully applied to an independent dataset from schizophrenia brains. Collectively, this study provided the first framework for systematically investigating trans-genetic effects of circQTLs and inferring the corresponding causal relations in diseases. The identified circQTL-circRNA-trans-eGene regulatory interactions, particularly the internal modules that were previously implicated in the examined disorders, also provided a helpful dataset for further investigating causative biology and cryptic regulatory mechanisms underlying the neuropsychiatric diseases.

自闭症谱系障碍 (ASD) 的遗传风险变异和转录表达变化得到了广泛研究，但它们之间的因果关系在很大程度上仍然未知。环状 RNA (circRNA) 在大脑中含量丰富，通常作为 mRNA 的上游调节因子。通过将 RNA 测序与来自自闭症大脑的基因型数据相结合，我们评估了 circRNA (circQTL) 的表达数量性状位点，该位点顺式调节附近 circRNA 的表达，同时反式调节远距离基因 ( trans -eGenes) 的表达。因此，我们鉴定了 3619 个也是反式-eQTL 的 circQTL，并构建了 19,804 个 circQTL-circRNA- trans-eGene 监管轴。我们进行了两种不同类型的方法，中介和偏相关检验 (MPT)，以确定 circQTL 通过 circRNA 表达对trans -eGene 表达的中介作用的轴。我们发现circQTLs（trans -eQTLs）对circRNA表达的中介作用与circRNA- trans -eGene表达谱相关性的大小呈正相关。在对 circQTL 进行调整后，正相关变得更加显着。在 19,804 个轴中，8103 个通过了 MPT。同时，我们进行了因果推理测试（CIT）并鉴定了 2070 个 circQTL- trans-eGene-ASD 诊断传播路径。我们发现 CIT 传递基因显着丰富了 ASD 风险基因、编码突触后密度蛋白的基因和其他 ASD 相关基因，支持 CIT 传递基因与 ASD 病理生理学的相关性。MPT-和CIT-传递轴的整合进一步构建了352个circQTL-circRNA- trans -eGene-ASD诊断传播路径，其中circRNA- trans -eGene轴可以作为circQTL-ASD诊断关联的因果中介。这些分析也成功地应用于精神分裂症大脑的独立数据集。总的来说，这项研究提供了第一个系统研究跨性别的框架-circQTLs的遗传效应并推断疾病中相应的因果关系。已确定的 circQTL-circRNA- trans -eGene 调控相互作用，特别是之前与检查的疾病有关的内部模块，也为进一步研究神经精神疾病的致病生物学和隐蔽调控机制提供了有用的数据集。