Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes

Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes

Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we perf...

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Published in:Nature neuroscience Vol. 25; no. 11; pp. 1559 - 1568
Main Authors: Benjamin, Kynon J. M., Chen, Qiang, Jaffe, Andrew E., Stolz, Joshua M., Collado-Torres, Leonardo, Huuki-Myers, Louise A., Burke, Emily E., Arora, Ria, Feltrin, Arthur S., Barbosa, André Rocha, Radulescu, Eugenia, Pergola, Giulio, Shin, Joo Heon, Ulrich, William S., Deep-Soboslay, Amy, Tao, Ran, Hyde, Thomas M., Kleinman, Joel E., Erwin, Jennifer A., Weinberger, Daniel R., Paquola, Apuã C. M.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01-11-2022
Nature Publishing Group
Subjects:
631/114/1305
631/208/212/2019
631/208/366
692/699/476/1799
Animal Genetics and Genomics
Antipsychotic Agents - pharmacology
Antipsychotic Agents - therapeutic use
Antipsychotics
Behavioral Sciences
Biological Techniques
Biomedical and Life Sciences
Biomedicine
Bipolar disorder
Caudate Nucleus
Dopamine
Dopamine D2 receptors
Drug development
Gene expression
Gene mapping
Genes
Genetic analysis
Genome-wide association studies
Genome-Wide Association Study
Genomes
Humans
Innervation
Mental disorders
Neostriatum
Neurobiology
Neurosciences
Psychotropic drugs
Quantitative trait loci
Resource
Risk analysis
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - genetics
Schizophrenia - metabolism
Therapeutic targets
Transcriptome
Transcriptomes
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Abstract Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. In this work, the authors transcriptionally and genetically profile 443 caudate nucleus samples, including 154 with schizophrenia, highlighting new genes associated with schizophrenia risk, including the presynaptic DRD2 isoform.
AbstractList Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum's dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.
Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.In this work, the authors transcriptionally and genetically profile 443 caudate nucleus samples, including 154 with schizophrenia, highlighting new genes associated with schizophrenia risk, including the presynaptic DRD2 isoform.
Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. In this work, the authors transcriptionally and genetically profile 443 caudate nucleus samples, including 154 with schizophrenia, highlighting new genes associated with schizophrenia risk, including the presynaptic DRD2 isoform.
Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum's dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum's dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.
Author Arora, Ria
Huuki-Myers, Louise A.
Chen, Qiang
Kleinman, Joel E.
Jaffe, Andrew E.
Shin, Joo Heon
Benjamin, Kynon J. M.
Tao, Ran
Hyde, Thomas M.
Erwin, Jennifer A.
Stolz, Joshua M.
Feltrin, Arthur S.
Barbosa, André Rocha
Collado-Torres, Leonardo
Pergola, Giulio
Burke, Emily E.
Ulrich, William S.
Radulescu, Eugenia
Weinberger, Daniel R.
Deep-Soboslay, Amy
Paquola, Apuã C. M.
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36319771$$D View this record in MEDLINE/PubMed
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Malhotra, Dheeraj
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Copyright The Author(s), under exclusive licence to Springer Nature America, Inc. 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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Snippet Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum...
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SubjectTerms 631/114/1305
631/208/212/2019
631/208/366
692/699/476/1799
Animal Genetics and Genomics
Antipsychotic Agents - pharmacology
Antipsychotic Agents - therapeutic use
Antipsychotics
Behavioral Sciences
Biological Techniques
Biomedical and Life Sciences
Biomedicine
Bipolar disorder
Caudate Nucleus
Dopamine
Dopamine D2 receptors
Drug development
Gene expression
Gene mapping
Genes
Genetic analysis
Genome-wide association studies
Genome-Wide Association Study
Genomes
Humans
Innervation
Mental disorders
Neostriatum
Neurobiology
Neurosciences
Psychotropic drugs
Quantitative trait loci
Resource
Risk analysis
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - genetics
Schizophrenia - metabolism
Therapeutic targets
Transcriptome
Transcriptomes
Title Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes
URI https://link.springer.com/article/10.1038/s41593-022-01182-7
https://www.ncbi.nlm.nih.gov/pubmed/36319771
https://www.proquest.com/docview/2731320577
https://www.proquest.com/docview/2731429728
Volume 25
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