Integrative Multiomics Analysis Identifies DKK3 as a Germline Susceptibility‐Related Regulator of Risperidone Response and Metabolic Risk in Schizophrenia

Background Risperidone is a widely used second‐generation antipsychotic for schizophrenia, known for its clinical efficacy but also for long‐term metabolic side effects, including weight gain and glucose–lipid dysregulation. Although its therapeutic effects have been well characterized, the molecular basis linking its benefits and adverse metabolic outcomes remains poorly understood. Methods To identify genes mediating both therapeutic and metabolic responses to risperidone, we conducted an integrative multiomics study combining large‐scale genetic association data with transcriptomic and epigenetic profiling. Differentially expressed genes following risperidone exposure were intersected with schizophrenia‐ and metabolism‐associated loci using summary data‐based Mendelian randomization analysis based on GWAS summary statistics and eQTL data to uncover germline variants, germline susceptibility, and potential germline alteration. DNA methylation profiling from patient‐derived peripheral blood mononuclear cells (PBMCs) was used for regulatory validation. Results We identified 120 genes significantly modulated by risperidone, among which DKK3, EEF1A1, and PRKAA1 were causally associated with schizophrenia and metabolic traits through germline mutation‐related regulatory evidence. Notably, DKK3 was downregulated after risperidone exposure and exhibited promoter hypermethylation, consistent with epigenetic regulation interacting with germline alteration and germline susceptibility. Functional correlation analysis revealed that lower DKK3 expression was associated with glycolipid dysregulation, supporting its role as a molecular bridge between antipsychotic action and metabolic liability. Conclusion Our findings identify DKK3 as a germline mutation‐related and epigenetically regulated candidate that bridges risperidone′s neuropsychiatric benefits with its metabolic risks. This work offers novel insight into the shared molecular basis of antipsychotic response and side effects and suggests DKK3 as a promising biomarker for personalized treatment strategies in schizophrenia informed by germline regulatory variation and potential germline alteration.