Longitudinal multi-omics alterations response to 8-week risperidone monotherapy: Evidence linking cortical thickness, transcriptomics and epigenetics

Xiaofen Zong; Gaohua Wang; Zhaowen Nie; Simeng Ma; Lijun Kang; Nan Zhang; Shenhong Weng; Qing Tan; Junjie Zheng; Maolin Hu

doi:10.3389/fpsyt.2023.1127353

Longitudinal multi-omics alterations response to 8-week risperidone monotherapy: Evidence linking cortical thickness, transcriptomics and epigenetics

Front Psychiatry. 2023 Mar 2:14:1127353. doi: 10.3389/fpsyt.2023.1127353. eCollection 2023.

Authors

Xiaofen Zong¹, Gaohua Wang¹, Zhaowen Nie¹, Simeng Ma¹, Lijun Kang¹, Nan Zhang¹, Shenhong Weng¹, Qing Tan^{2

3}, Junjie Zheng^{4

5}, Maolin Hu^{1

6

7}

Affiliations

¹ Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
² School of Mathematics and Statistics, Wuhan University, Wuhan, Hubei, China.
³ Hubei Key Laboratory of Computational Science, Wuhan University, Wuhan, Hubei, China.
⁴ The Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
⁵ The Functional Brain Imaging Institute, Nanjing Medical University, Nanjing, Jiangsu, China.
⁶ Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁷ Department of Psychiatry, Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Allen Human Brain Atlas; DNA methylation; cortical thickness; magnetic resonance imaging; risperidone; schizophrenia.

Grants and funding

This research was funded by the National Natural Science Foundation of China (No. 81901357), the National Key Research and Development Program of China (STI2030-Major Projects, 2021ZD0202000), and the College Students' Innovative Entrepreneurial Training Plan Program (No. S202210486266).