Genomics Research Center, Academia Sinica, Taipei, 115201, Taiwan.
Department of Life Science, National Taiwan University, Taipei, 106319, Taiwan.
Mol Psychiatry. 2022 Nov;27(11):4695-4706. doi: 10.1038/s41380-022-01714-4. Epub 2022 Aug 12.
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.
在自闭症谱系障碍 (ASD) 中，广泛研究了遗传风险变异和转录表达变化，但它们的因果关系仍知之甚少。环状 RNA (circRNA) 在大脑中丰富存在，通常作为 mRNA 的上游调节剂。通过将 RNA 测序与自闭症大脑的基因型数据相结合，我们评估了circRNA 的表达数量性状基因座 (circQTL)，这些基因座同时顺式调节附近 circRNA 的表达和反式调节远处基因的表达 (trans-eGenes)。因此，我们鉴定了 3619 个同时为 circQTL 和 trans-eQTL 的 circRNA，构建了 19804 个 circQTL-circRNA-trans-eGene 调控轴。我们进行了两种不同的方法，中介和部分相关测试 (MPT)，以确定通过 circRNA 表达介导 circQTL 对 trans-eGene 表达的轴。我们表明，circQTL（trans-eQTL）对 circRNA 表达的中介效应与 circRNA-trans-eGene 表达谱相关性的大小呈正相关。在调整 circQTL 后，这种正相关变得更加显著。在 19804 个轴中，有 8103 个通过了 MPT。同时，我们进行了因果推断测试 (CIT)，并鉴定了 2070 个 circQTL-trans-eGene-ASD 诊断传播路径。我们表明，CIT 传递的基因显著富集了 ASD 风险基因、编码突触后密度蛋白的基因和其他与 ASD 相关的基因，支持 CIT 传递的基因与 ASD 病理生理学的相关性。整合 MPT 和 CIT 传递的轴进一步构建了 352 个 circQTL-circRNA-trans-eGene-ASD 诊断传播路径，其中 circRNA-trans-eGene 轴可能作为 circQTL-ASD 诊断关联的因果介导物。这些分析也成功应用于来自精神分裂症大脑的独立数据集。总的来说，这项研究为系统地研究 circQTL 的反式遗传效应并推断疾病中相应的因果关系提供了第一个框架。鉴定的 circQTL-circRNA-trans-eGene 调控相互作用，特别是那些先前涉及所研究疾病的内部模块，也为进一步研究神经精神疾病的因果生物学和隐匿调控机制提供了一个有帮助的数据集。
