Methylome-wide association study of different responses to risperidone in schizophrenia

Huihui Du; Jingsong Ma; Wei Zhou; Mo Li; Cong Huai; Lu Shen; Hao Wu; Xianglong Zhao; Na Zhang; Songyin Gao; Qi Wang; Lin He; Xuming Wu; Shengying Qin; Mingzhe Zhao

doi:10.3389/fphar.2022.1078464

Methylome-wide association study of different responses to risperidone in schizophrenia

Front Pharmacol. 2022 Dec 22:13:1078464. doi: 10.3389/fphar.2022.1078464. eCollection 2022.

Authors

Huihui Du¹, Jingsong Ma^{2

3}, Wei Zhou¹, Mo Li¹, Cong Huai¹, Lu Shen¹, Hao Wu¹, Xianglong Zhao¹, Na Zhang¹, Songyin Gao⁴, Qi Wang⁵, Lin He¹, Xuming Wu⁶, Shengying Qin¹, Mingzhe Zhao^{1

7}

Affiliations

¹ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
² School o f Engineering, Westlake University, Hangzhou, Zhejiang, China.
³ Institute of Advanced Technology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
⁴ Zhumadian Psychiatric Hospital, Zhumadian, China.
⁵ Hebei Mental Health Center, Hebei Sixth People's Hospital, Baoding, China.
⁶ Nantong Fourth People's Hospital, Nantong, China.
⁷ Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Background: Accumulating evidence shows that DNA methylation plays a role in antipsychotic response. However, the mechanisms by which DNA methylation changes are associated with antipsychotic responses remain largely unknown. Methods: We performed a methylome-wide association study (MWAS) to evaluate the association between DNA methylation and the response to risperidone in schizophrenia. Genomic DNA methylation patterns were assessed using the Agilent Human DNA Methylation Microarray. Results: We identified numerous differentially methylated positions (DMPs) and regions (DMRs) associated with antipsychotic response. CYP46A1, SPATS2, and ATP6V1E1 had the most significant DMPs, with p values of 2.50 × 10^-6, 3.53 × 10^-6, and 5.71 × 10^-6, respectively. The top-ranked DMR was located on chromosome 7, corresponding to the PTPRN2 gene with a Šidák-corrected p-value of 9.04 × 10^-13. Additionally, a significant enrichment of synaptic function and neurotransmitters was found in the differentially methylated genes after gene ontology and pathway analysis. Conclusion: The identified DMP- and DMR-overlapping genes associated with antipsychotic response are related to synaptic function and neurotransmitters. These findings may improve understanding of the mechanisms underlying antipsychotic response and guide the choice of antipsychotic in schizophrenia.

Keywords: DMP; DMR; MWAS; antipsychotic response; pharmacoepigenomics.