The neurodevelopmental regulatory role and clinical value of the multi-molecular axis in early-onset schizophrenia [miRNA]

Background: Biomarkers identified by previous epigenetic studies of schizophrenia have focused solely on diagnostics or pathology, potentially leading to a disconnection between them. This study focused on early-onset schizophrenia (EOS), aiming to identify the multi-molecular axis centered on circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) with both neurobiological function and diagnostic value. Methods: Based on the discovery cohort and validation cohort-1, screening of candidate genes on the axis were completed via high-throughput sequencing, expressive and structural validation. Combining dual-luciferase reporter assays with overexpression/knockdown experiments, the axis with binding and regulatory relationships has been established. Subsequently, the functions of genes on the axis were explored through zebrafish embryo manipulation and neural differentiation. The clinical value of the entire axis was assessed in the validation cohort-2. Results: The regulatory effects of hsa-circ-CORO1C on hsa-miR-708-3p, hsa-miR-708-3p on target JARID2 and LNPEP were elucidated. Among them, hsa-miR-708-3p caused aberrant phenotypes including significant craniocerebral malformation and impaired neuron axon growth. JARID2 and LNPEP could facilitate neuronal differentiation and augment synaptic formation. The combined diagnostic efficacy of the whole axis, where hsa-circ-CORO1C could serve as a sponge for hsa-miR-708-3p to alleviate its suppressive effects on JARID2 and LNPEP, surpassed any individual gene we found in EOS. Conclusions: Our study demonstrated a multi-molecular axis, hsa-circ-CORO1C–hsa-miR-708-3p–JARID2+LNPEP, in EOS for the first time. By integrating evidence from genetic, neurophenotypic, and clinical perspectives, we have expanded the comprehension of the pathological mechanism and provided the reference for identifying reliable objective diagnostic biomarkers for EOS. In the cohort of 10 drug-naïve, first-episode patients with early-onset schizophrenia and 10 matched healthy controls, differentially expressed circRNAs and miRNAs were identified via Illumina high-throughput sequencing.

研究背景：既往精神分裂症表观遗传学研究筛选出的生物标志物（biomarkers）仅聚焦于诊断或病理层面，这可能导致各类标志物之间缺乏关联。本研究针对早发性精神分裂症（early-onset schizophrenia, EOS）展开，旨在筛选同时具备神经生物学功能与诊断价值的、以环状RNA（circular RNAs, circRNAs）、微小RNA（microRNAs, miRNAs）及信使RNA（messenger RNAs, mRNAs）为核心的多分子调控轴。
研究方法：基于发现队列与验证队列1，本研究通过高通量测序、表达及结构验证完成了该调控轴上候选分子的筛选。结合双荧光素酶报告基因实验与过表达/敲低实验，本研究构建了具备结合与调控关系的该多分子调控轴。随后，通过斑马鱼胚胎操作与神经分化实验，本研究探究了该调控轴上分子的生物学功能。最后在验证队列2中评估了整个调控轴的临床诊断价值。
研究结果：本研究阐明了hsa-circ-CORO1C对hsa-miR-708-3p的调控作用，以及hsa-miR-708-3p对靶基因JARID2与LNPEP的调控作用。其中，hsa-miR-708-3p可引发异常表型，包括显著的颅脑畸形与神经元轴突生长受损。JARID2与LNPEP则可促进神经分化并增强突触形成。此外，hsa-circ-CORO1C可作为hsa-miR-708-3p的海绵分子，缓解其对JARID2与LNPEP的抑制作用；整个调控轴的联合诊断效能优于本研究在EOS中发现的任一单一分子。
研究结论：本研究首次在EOS中发现了一条多分子调控轴——hsa-circ-CORO1C–hsa-miR-708-3p–JARID2+LNPEP。本研究整合遗传学、神经表型与临床多维度证据，深化了对EOS病理机制的理解，并为筛选可靠的客观诊断生物标志物提供了参考依据。本研究在10例未接受过药物治疗的首发EOS患者与10例匹配的健康对照者组成的队列中，通过Illumina高通量测序筛选出了差异表达的circRNAs与miRNAs。