Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia
Abstract Background Antipsychotic-induced movement disorders (AIMDs) are prevalent side effects of antipsychotics, particularly during the acute phase of treatment. This study aimed to elucidate the genetic mechanisms underlying AIMDs using a genome-wide association study (GWAS). Methods GWASs on AI...
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2025-08-01
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| Online Access: | https://doi.org/10.1186/s40779-025-00636-w |
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| author | Zhe Lu Yao-Yao Sun Zhe-Wei Kang Guo-Rui Zhao Yu-Yanan Zhang Jun-Yuan Sun Rui Yuan Wei-Hua Yue |
| author_facet | Zhe Lu Yao-Yao Sun Zhe-Wei Kang Guo-Rui Zhao Yu-Yanan Zhang Jun-Yuan Sun Rui Yuan Wei-Hua Yue |
| author_sort | Zhe Lu |
| collection | DOAJ |
| description | Abstract Background Antipsychotic-induced movement disorders (AIMDs) are prevalent side effects of antipsychotics, particularly during the acute phase of treatment. This study aimed to elucidate the genetic mechanisms underlying AIMDs using a genome-wide association study (GWAS). Methods GWASs on AIMDs were conducted in 3 independent cohorts: a discovery cohort of 3067 patients (2016 subjects were reserved after quality control), a validation cohort of 277 patients, and a multi-ancestry validation cohort of 766 patients. Subsequent post-GWAS analyses included gene-based analyses, transcriptome-wide association studies (TWASs), and polygenic risk score (PRS) profiling. Results Our study identified 2 loci located in RAB44 gene (rs116249243, P = 5.98 × 10–9; rs117097482, P = 1.17 × 10–8) associated with extrapyramidal symptoms (EPSs), 1 locus (rs6826172, P = 5.56 × 10–9) related to akathisia, and 76 loci linked to involuntary movements (11 genes were mapped). Risk loci located in CNTNAP2, LUZP2, TMEM167A, and RAB44 genes were successfully replicated in the validation cohort, whereas the locus located in RAB44 was also replicated in the multi-ancestry cohort. Gene-based analyses indicated that XRCC4 and PAIP2B reached significance at the genome-wide level in involuntary movements. Tissue expression analysis revealed that involuntary movement-related genes are predominantly expressed in the substantia nigra. Additionally, the TWAS suggested a causal relationship between XRCC4 and involuntary movement. The PRSs derived from the discovery cohort significantly predicted AIMDs in the validation cohort, with area under the receiver operating characteristic curve (AUC) values from 0.60 to 0.80. Conclusions Our findings highlight the role of substantia nigra related gene polymorphisms in AIMDs. This study provides novel insights into the pathogenesis of AIMDs and supports the potential for personalized treatment approaches for schizophrenia. Trial registration ChiCTR ( https://www.chictr.org.cn/showproj.html?proj=8604 ), No. ChiCTR-TRC-10000934; ChiCTR ( https://www.chictr.org.cn/showproj.html?proj=129668 ), No. ChiCTR2100048320. |
| format | Article |
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| institution | Kabale University |
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| publishDate | 2025-08-01 |
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| series | Military Medical Research |
| spelling | doaj-art-b6777bc7219a4b5b80f1fa74f6d9c0c32025-08-24T11:14:48ZengBMCMilitary Medical Research2054-93692025-08-0112111310.1186/s40779-025-00636-wSubstantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophreniaZhe Lu0Yao-Yao Sun1Zhe-Wei Kang2Guo-Rui Zhao3Yu-Yanan Zhang4Jun-Yuan Sun5Rui Yuan6Wei-Hua Yue7Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalPeking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth HospitalAbstract Background Antipsychotic-induced movement disorders (AIMDs) are prevalent side effects of antipsychotics, particularly during the acute phase of treatment. This study aimed to elucidate the genetic mechanisms underlying AIMDs using a genome-wide association study (GWAS). Methods GWASs on AIMDs were conducted in 3 independent cohorts: a discovery cohort of 3067 patients (2016 subjects were reserved after quality control), a validation cohort of 277 patients, and a multi-ancestry validation cohort of 766 patients. Subsequent post-GWAS analyses included gene-based analyses, transcriptome-wide association studies (TWASs), and polygenic risk score (PRS) profiling. Results Our study identified 2 loci located in RAB44 gene (rs116249243, P = 5.98 × 10–9; rs117097482, P = 1.17 × 10–8) associated with extrapyramidal symptoms (EPSs), 1 locus (rs6826172, P = 5.56 × 10–9) related to akathisia, and 76 loci linked to involuntary movements (11 genes were mapped). Risk loci located in CNTNAP2, LUZP2, TMEM167A, and RAB44 genes were successfully replicated in the validation cohort, whereas the locus located in RAB44 was also replicated in the multi-ancestry cohort. Gene-based analyses indicated that XRCC4 and PAIP2B reached significance at the genome-wide level in involuntary movements. Tissue expression analysis revealed that involuntary movement-related genes are predominantly expressed in the substantia nigra. Additionally, the TWAS suggested a causal relationship between XRCC4 and involuntary movement. The PRSs derived from the discovery cohort significantly predicted AIMDs in the validation cohort, with area under the receiver operating characteristic curve (AUC) values from 0.60 to 0.80. Conclusions Our findings highlight the role of substantia nigra related gene polymorphisms in AIMDs. This study provides novel insights into the pathogenesis of AIMDs and supports the potential for personalized treatment approaches for schizophrenia. Trial registration ChiCTR ( https://www.chictr.org.cn/showproj.html?proj=8604 ), No. ChiCTR-TRC-10000934; ChiCTR ( https://www.chictr.org.cn/showproj.html?proj=129668 ), No. ChiCTR2100048320.https://doi.org/10.1186/s40779-025-00636-wAntipsychoticMovement disordersGenome-wide association study (GWAS)Substantia nigraMulti-ancestry validation |
| spellingShingle | Zhe Lu Yao-Yao Sun Zhe-Wei Kang Guo-Rui Zhao Yu-Yanan Zhang Jun-Yuan Sun Rui Yuan Wei-Hua Yue Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia Military Medical Research Antipsychotic Movement disorders Genome-wide association study (GWAS) Substantia nigra Multi-ancestry validation |
| title | Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia |
| title_full | Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia |
| title_fullStr | Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia |
| title_full_unstemmed | Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia |
| title_short | Substantia nigra related gene polymorphisms associated with antipsychotic-induced acute movement disorders: a genome-wide association study and multi-ancestry validation in schizophrenia |
| title_sort | substantia nigra related gene polymorphisms associated with antipsychotic induced acute movement disorders a genome wide association study and multi ancestry validation in schizophrenia |
| topic | Antipsychotic Movement disorders Genome-wide association study (GWAS) Substantia nigra Multi-ancestry validation |
| url | https://doi.org/10.1186/s40779-025-00636-w |
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