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

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.

We thank all participants who participated in this study. This work was supported by the Capital’s Funds for Health Improvement and Research (grant number 2024-1-4111); National Natural Science Foundation of China (grant numbers 82101571, 82330042); National Key R&D Program of China (grant numbers 2023YFE0119400, 2021YFF1201100); Supported by the Open Project of Psychiatry and Neuroscience Discipline of Second Affiliated Hospital of Henan Medical University (grant number No. Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China Xueping Wang, Zhewei Kang, Yuyanan Zhang, Yaoyao Sun, Tianlan Lu, Hao Yan & Weihua Yue National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) & NHC Key Laboratory of Mental Health (Peking University), Beijing, China PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China The authors declare no competing interests.

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