Data_Sheet_1_Predictive Biomarkers for Antipsychotic Treatment Response in Early Phase of Schizophrenia: Multi-Omic Measures Linking Subcortical Covariant Network, Transcriptomic Signatures, and Peripheral Epigenetics.docx

BackgroundVolumetric alterations of subcortical structures as predictors of antipsychotic treatment response have been previously corroborated, but less is known about whether their morphological covariance relates to treatment outcome and is driven by gene expression and epigenetic modifications. MethodsSubcortical volumetric covariance was analyzed by using baseline T1-weighted magnetic resonance imaging (MRI) in 38 healthy controls and 38 drug-naïve first-episode schizophrenia patients. Patients were treated with 8-week risperidone monotherapy and divided into responder and non-responder groups according to the Remission in Schizophrenia Working Group (RSWG). We utilized partial least squares (PLS) regression to examine the spatial associations between gene expression of subcortical structures from a publicly available transcriptomic dataset and between-group variances of structural covariance. The peripheral DNA methylation (DNAm) status of a gene of interest (GOI), overlapping between genes detected in the PLS and 108 schizophrenia candidate gene loci previously reported, was examined in parallel with MRI scanning. ResultsIn the psychotic symptom dimension, non-responders had a higher baseline structural covariance in the putamen–hippocampus–pallidum–accumbens pathway compared with responders. For disorganized symptoms, significant differences in baseline structural covariant connections were found in the putamen–hippocampus–pallidum–thalamus circuit between the two subgroups. The imaging variances related to psychotic symptom response were spatially related to the expression of genes enriched in neurobiological processes and dopaminergic pathways. The DNAm of GOI demonstrated significant associations with patients’ improvement of psychotic symptoms. ConclusionBaseline subcortical structural covariance and peripheral DNAm may relate to antipsychotic treatment response. Phenotypic variations in subcortical connectome related to psychotic symptom response may be transcriptomically and epigenetically underlaid. This study defines a roadmap for future studies investigating multimodal imaging epigenetic biomarkers for treatment response in schizophrenia.【背景】皮层下结构的体积改变可作为抗精神病药物治疗应答的预测因子，这一点此前已得到证实，但目前尚不清楚其形态协变是否与治疗结局相关，以及是否由基因表达与表观遗传修饰所驱动。 【方法】本研究纳入38名健康对照者与38名初治首发精神分裂症患者，利用基线T1加权磁共振成像（MRI）分析其皮层下体积协变特征。患者接受为期8周的利培酮单药治疗，并依据精神分裂症缓解工作组（Remission in Schizophrenia Working Group, RSWG）标准分为应答组与无应答组。我们采用偏最小二乘（PLS）回归，分析来自公开转录组数据集的皮层下结构基因表达与结构协变的组间差异之间的空间关联。同时，在MRI扫描同期，检测本研究关注的基因（gene of interest, GOI）的外周血DNA甲基化（DNAm）状态；该基因需同时满足两个条件：一是在PLS分析中被检出，二是属于此前已报道的108个精神分裂症候选基因位点。 【结果】在精神病性症状维度上，无应答组患者的壳核-海马-苍白球-伏隔核通路基线结构协变水平显著高于应答组。针对瓦解症状群，两组受试者的基线结构协变连接在壳核-海马-苍白球-丘脑环路中存在显著差异。与精神病性症状应答相关的影像学差异，在空间分布上与富集于神经生物学过程及多巴胺能通路的基因表达相关。本研究关注基因的DNAm水平与患者精神病性症状的改善程度存在显著关联。 【结论】基线皮层下结构协变与外周血DNA甲基化水平或与抗精神病药物治疗应答相关。与精神病性症状应答相关的皮层下连接组表型变异，可能在转录组学与表观遗传学层面存在调控基础。本研究为未来探索精神分裂症治疗应答的多模态成像表观遗传生物标志物的相关研究提供了研究框架。