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

Abstract

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.

Integrative omics analysis reveals epigenomic and transcriptomic signatures underlying brain structural deficits in major depressive disorder

“…The imaging transcriptomic analysis was used as the feature selection strategy to identify brain-wide GMV change-related genes and further reduce the high dimensions of the candidate CpG sites. The imaging transcriptional analysis is a versatile method for feature selection in our previous imaging genetic studies [ 42 , 43 ]. In addition, the PCR method could examine both common and region-specific DMPs associated with GMV changes.…”

Epigenetic clock analysis of blood samples in drug-naive first-episode schizophrenia patients

“…Left and right accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, as well as intracranial volume (ICVs), were obtained from high-resolution T1-weighted structural brain data by using the programme’s segmentation procedure of FreeSurfer software package (v5.3.0, http://surfer.nmr.mgh.harvard.edu ). Details on acquisition parameters and image processing are described in our previous study [ 40 ].…”

Striatum-related spontaneous coactivation patterns predict treatment response on positive symptoms of drug-naive first-episode schizophrenia with risperidone monotherapy

“…We recruited 42 treatment-naive patients with first-episode schizophrenia (Patients-0W) and 38 education-, gender-, and age- matched healthy controls in the Second Affiliated Hospital of Xinxiang Medical University in China from 2012.12 to 2014.01, China. This fMRI dataset has been used previously by our group ( 22 , 23 ). Experienced psychiatrists diagnosed patients according to the Structured Clinical Interview for DSM-IV-TR.…”