AUTHOR=Zong Xiaofen , He Changchun , Huang Xinyue , Xiao Jinming , Li Lei , Li Meiling , Yao Tao , Hu Maolin , Liu Zhongchun , Duan Xujun , Zheng Junjie 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 16 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.853186

DOI=10.3389/fnins.2022.853186

ISSN=1662-453X

ABSTRACT=Background: Volumetric 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.
Methods: Subcortical volumetric covariance was analysed 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 criteria of the Schizophrenia Working Group. 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 genes 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.
Results: In the psychotic symptom dimension, nonresponders had a higher baseline structural covariance in the putamen-hippocampus-pallidum-accumben 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 expression of genes enriched in neurobiological processes and dopaminergic pathways. The DNAm of GOI demonstrated significant associations with patients’ improvement of psychotic symptoms.
Conclusion: Subcortical structural covariance and peripheral DNAm could be useful predictors of antipsychotic treatment response. Phenotypic variations in subcortical connectome related to psychotic symptom response may be transcriptomically and epigenetically underlied. This study defines a roadmap for future researches investigating multi-modal imaging epigenetics biomarkers for treatment response in schizophrenia.