Exploratory genetic and expression analysis identifies MCTP2 associated with negative symptom improvement in schizophrenia

Abstract Negative symptoms are common initial manifestations of schizophrenia, and their improvement is key to social function prognosis. MCTP2, a C2 domain-containing protein, is involved in higher cognitive functions and critical for facial recognition. We hypothesized MCTP2 may be associated with negative symptom improvement in schizophrenia patients receiving antipsychotics. A genome-wide association study was performed in Han Chinese schizophrenia patients to explore the association between genetic polymorphisms and antipsychotic response, focusing on PANSS negative (PANSS-N) symptom reduction after 6-week aripiprazole or ziprasidone monotherapy. The eQTL gene expression, protein–protein interaction network, and network pharmacology analyses were conducted to clarify the regulatory mechanism and molecular networks. An association was identified between MCTP2 polymorphism rs28502452 ( P = 8.01×10⁻⁶) and PANSS-N symptom reduction. Patients with alleles linked to higher MCTP2 expression had greater PANSS-N reduction. Expression analyses in schizophrenia, Alzheimer’s disease and autism confirmed MCTP2’s positive regulation of normal cognitive functions. Protein–protein interaction analysis revealed a calcium signaling cluster (SLITRK5, NCALD, CPNE5), and the calcium signaling pathway is major in the network pharmacology of aripiprazole and ziprasidone. Furthermore, synaptic proteins SLITRK5 and PTPRD may regulate the interaction network between MCTP2 and BTBD9, the latter two of which are high-risk genes for improving negative symptoms. This study demonstrates MCTP2’s involvement in schizophrenia negative symptoms, confirms its positive role in cognitive function, and identifies the synaptic calcium signaling network. These findings provide a foundation for future research on negative symptoms, cognitive impairment, and targeted therapies.