Risperidone Response and Metabolic Risk Linked to DKK3 Regulation via Germline Susceptibility and Epigenetics

Second-generation antipsychotics like risperidone are crucial for treating schizophrenia, offering significant clinical efficacy. However, their long-term use is frequently complicated by severe metabolic side effects, including weight gain, obesity, and glucose-lipid dysregulation. This antipsychotic-induced metabolic dysfunction significantly impacts patient adherence and overall health. The precise molecular mechanisms connecting risperidone's therapeutic benefits with its adverse metabolic outcomes have remained largely elusive, representing a critical gap in understanding and managing treatment.

To identify genes mediating both therapeutic and metabolic responses to risperidone, researchers conducted an integrative multiomics study. This combined large-scale genetic association data with transcriptomic and epigenetic profiling. They used summary data-based Mendelian randomization analysis, leveraging GWAS summary statistics and eQTL data to uncover germline variants and susceptibility. DNA methylation profiling from patient-derived peripheral blood mononuclear cells (PBMCs) was employed for regulatory validation of these findings.

The analysis identified 120 genes significantly modulated by risperidone exposure. Among these, DKK3, EEF1A1, and PRKAA1 were causally associated with both schizophrenia and metabolic traits, supported by germline mutation-related regulatory evidence. > Notably, DKK3 was consistently downregulated after risperidone exposure and exhibited promoter hypermethylation, indicating epigenetic regulation interacting with germline alterations. Functional correlation analysis further demonstrated that lower DKK3 expression was directly associated with glycolipid dysregulation, reinforcing its role as a molecular bridge between antipsychotic action and metabolic liability.