{"title":"通过网络分析识别和优先排序与精神分裂症风险相关的基因集。","authors":"Minglan Yu, Qingyu Tan, Wei Dong, Bo Xiang","doi":"10.1007/s00213-025-06867-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>Genome-wide association studies (GWASs) are used to identify genetic variants for association with schizophrenia (SCZ) risk; however, each GWAS can only reveal a small fraction of this association.</p><p><strong>Objectives: </strong>This study systematically analyzed multiple GWAS data sets to identify gene subnetwork and pathways associated with SCZ.</p><p><strong>Methods: </strong>We identified gene subnetwork using dmGWAS program by combining SCZ GWASs and a human interaction network, performed gene-set analysis to test the association of gene subnetwork with clinical symptom scores and disease state, meanwhile, conducted spatiotemporal and tissue-specific expression patterns and cell-type-specific analysis of genes in the subnetwork.</p><p><strong>Results: </strong>We identified a gene subnetwork comprising 48 genes was associated with SCZ, and confirmed gene subnetwork's gene-set association with SCZ (Case vs. Control) in two independent cohorts. Gene prioritization identified CALM1 and TCF4 as hub genes in the subnetwork. Meanwhile, using gene-set analysis, it was determined that the gene subnetwork was also linked to generality symptoms and Positive and Negative Syndrome Scale (PANSS) total score in SCZ. 12 out of 48 genes were higher expression in early prenatal brain. In addition, expressions of CALM1, NCAM1, and TCF4 were dysregulated in cerebral organoids of SCZ patients compared with healthy controls. CALM1 and NCAM1 were mainly expressed on the surface of glutamatergic neurons.</p><p><strong>Conclusions: </strong>Our findings identified CALM1, NCAM1, and TCF4 as SCZ risk genes and provided important clues to support the neurodevelopmental hypothesis and new therapeutic targets of SCZ.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification and prioritization of gene sets associated with schizophrenia risk by network analysis.\",\"authors\":\"Minglan Yu, Qingyu Tan, Wei Dong, Bo Xiang\",\"doi\":\"10.1007/s00213-025-06867-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>Genome-wide association studies (GWASs) are used to identify genetic variants for association with schizophrenia (SCZ) risk; however, each GWAS can only reveal a small fraction of this association.</p><p><strong>Objectives: </strong>This study systematically analyzed multiple GWAS data sets to identify gene subnetwork and pathways associated with SCZ.</p><p><strong>Methods: </strong>We identified gene subnetwork using dmGWAS program by combining SCZ GWASs and a human interaction network, performed gene-set analysis to test the association of gene subnetwork with clinical symptom scores and disease state, meanwhile, conducted spatiotemporal and tissue-specific expression patterns and cell-type-specific analysis of genes in the subnetwork.</p><p><strong>Results: </strong>We identified a gene subnetwork comprising 48 genes was associated with SCZ, and confirmed gene subnetwork's gene-set association with SCZ (Case vs. Control) in two independent cohorts. Gene prioritization identified CALM1 and TCF4 as hub genes in the subnetwork. Meanwhile, using gene-set analysis, it was determined that the gene subnetwork was also linked to generality symptoms and Positive and Negative Syndrome Scale (PANSS) total score in SCZ. 12 out of 48 genes were higher expression in early prenatal brain. In addition, expressions of CALM1, NCAM1, and TCF4 were dysregulated in cerebral organoids of SCZ patients compared with healthy controls. CALM1 and NCAM1 were mainly expressed on the surface of glutamatergic neurons.</p><p><strong>Conclusions: </strong>Our findings identified CALM1, NCAM1, and TCF4 as SCZ risk genes and provided important clues to support the neurodevelopmental hypothesis and new therapeutic targets of SCZ.</p>\",\"PeriodicalId\":20783,\"journal\":{\"name\":\"Psychopharmacology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00213-025-06867-y\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00213-025-06867-y","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Identification and prioritization of gene sets associated with schizophrenia risk by network analysis.
Rationale: Genome-wide association studies (GWASs) are used to identify genetic variants for association with schizophrenia (SCZ) risk; however, each GWAS can only reveal a small fraction of this association.
Objectives: This study systematically analyzed multiple GWAS data sets to identify gene subnetwork and pathways associated with SCZ.
Methods: We identified gene subnetwork using dmGWAS program by combining SCZ GWASs and a human interaction network, performed gene-set analysis to test the association of gene subnetwork with clinical symptom scores and disease state, meanwhile, conducted spatiotemporal and tissue-specific expression patterns and cell-type-specific analysis of genes in the subnetwork.
Results: We identified a gene subnetwork comprising 48 genes was associated with SCZ, and confirmed gene subnetwork's gene-set association with SCZ (Case vs. Control) in two independent cohorts. Gene prioritization identified CALM1 and TCF4 as hub genes in the subnetwork. Meanwhile, using gene-set analysis, it was determined that the gene subnetwork was also linked to generality symptoms and Positive and Negative Syndrome Scale (PANSS) total score in SCZ. 12 out of 48 genes were higher expression in early prenatal brain. In addition, expressions of CALM1, NCAM1, and TCF4 were dysregulated in cerebral organoids of SCZ patients compared with healthy controls. CALM1 and NCAM1 were mainly expressed on the surface of glutamatergic neurons.
Conclusions: Our findings identified CALM1, NCAM1, and TCF4 as SCZ risk genes and provided important clues to support the neurodevelopmental hypothesis and new therapeutic targets of SCZ.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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