抗精神病药物治疗相关的大脑皮层厚度与临床症状的变化已经得到证实，但目前关于这些变化是否由基因表达和表观遗传修饰引起的认识较少。本研究采用前瞻性设计，招募了42例未接受过治疗的首发精神分裂症患者和38位健康对照者。在八周利培酮单一治疗前后，对患者进行 TI 加权成像扫描。利用 FreeSurfer 软件包进行 CT 估计。同时，使用 Infinium® 人类甲基化 450K BeadChip 检测 T1 扫描时参与者的外周血基因组 DNA 甲基化状态。共收集了118名受试者的 CT 测量和114名受试者的基因组 DNA 甲基化状态。采用部分最小二乘回归分析发现长期治疗后 CT 变化与 Allen 人类脑图谱获取的皮层转录组数据之间存在空间关联。接着，进行规范相关分析，发现 PLS1 基因的 DNA 甲基化与患者的临床改善率存在多元关联。我们发现了与 CT 变化有关的显著 PLS1 成分（2098个基因），而这些 PLS1 基因在神经生物学过程、多巴胺和癌症相关通路中显著富集。通过拉普拉斯分数和 CCA 分析，我们进一步将这些 2098 个 PLS1 基因中的 33 个代表基因与患者的临床症状缓解率联系起来。本研究首次揭示了治疗后 CT 和临床行为的改变可能是转录和表观遗传学机制所致。我们定义了一项“三步”路线图，旨在通过基于多重组学而非单一组学类型的策略，探索与治疗及治疗反应相关的生物标志物，并推进精准治疗。版权所有©2023年宗，王，聂，马，康，张，翁，谭，郑和胡。

Antipsychotic treatment-related alterations of cortical thickness (CT) and clinical symptoms have been previously corroborated, but less is known about whether the changes are driven by gene expression and epigenetic modifications.Utilizing a prospective design, we recruited 42 treatment-naive first-episode schizophrenia patients (FESP) and 38 healthy controls. Patients were scanned by TI weighted imaging before and after 8-week risperidone monotherapy. CT estimation was automatically performed with the FreeSurfer software package. Participants' peripheral blood genomic DNA methylation (DNAm) status, quantified by using Infinium® Human Methylation 450K BeadChip, was examined in parallel with T1 scanning. In total, CT measures from 118 subjects and genomic DNAm status from 114 subjects were finally collected. Partial least squares (PLS) regression was used to detect the spatial associations between longitudinal CT variations after treatment and cortical transcriptomic data acquired from the Allen Human Brain Atlas. Canonical correlation analysis (CCA) was then performed to identify multivariate associations between DNAm of PLS1 genes and patients' clinical improvement.We detected the significant PLS1 component (2,098 genes) related to longitudinal alterations of CT, and the PLS1 genes were significantly enriched in neurobiological processes, and dopaminergic- and cancer-related pathways. Combining Laplacian score and CCA analysis, we further linked DNAm of 33 representative genes from the 2,098 PLS1 genes with patients' reduction rate of clinical symptoms.This study firstly revealed that changes of CT and clinical behaviors after treatment may be transcriptionally and epigenetically underlied. We define a "three-step" roadmap which represents a vital step toward the exploration of treatment- and treatment response-related biomarkers on the basis of multiple omics rather than a single omics type as a strategy for advancing precise care.Copyright © 2023 Zong, Wang, Nie, Ma, Kang, Zhang, Weng, Tan, Zheng and Hu.