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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| Veröffentlicht in: | Nature neuroscience 2022-11, Vol.25 (11), p.1559-1568 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1038/s41593-022-01182-7 |
| format | Article |
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DRD2
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M.</creatorcontrib><creatorcontrib>BrainSeq Consortium</creatorcontrib><creatorcontrib>the BrainSeq Consortium</creatorcontrib><title>Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><addtitle>Nat Neurosci</addtitle><description>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. 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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.</description><subject>631/114/1305</subject><subject>631/208/212/2019</subject><subject>631/208/366</subject><subject>692/699/476/1799</subject><subject>Animal Genetics and Genomics</subject><subject>Antipsychotic Agents - pharmacology</subject><subject>Antipsychotic Agents - therapeutic use</subject><subject>Antipsychotics</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bipolar disorder</subject><subject>Caudate Nucleus</subject><subject>Dopamine</subject><subject>Dopamine D2 receptors</subject><subject>Drug development</subject><subject>Gene expression</subject><subject>Gene mapping</subject><subject>Genes</subject><subject>Genetic analysis</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Humans</subject><subject>Innervation</subject><subject>Mental disorders</subject><subject>Neostriatum</subject><subject>Neurobiology</subject><subject>Neurosciences</subject><subject>Psychotropic drugs</subject><subject>Quantitative trait loci</subject><subject>Resource</subject><subject>Risk analysis</subject><subject>Schizophrenia</subject><subject>Schizophrenia - drug therapy</subject><subject>Schizophrenia - genetics</subject><subject>Schizophrenia - metabolism</subject><subject>Therapeutic targets</subject><subject>Transcriptome</subject><subject>Transcriptomes</subject><issn>1097-6256</issn><issn>1546-1726</issn><issn>1546-1726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU2L1TAUhoMozof-ARcScOOmmo8maZbDoI4w4EbXJTc9uc3Ym9ac1OH6B_zbZqajggshh-SQ57yBPIS84OwNZ7J7iy1XVjZMiIZx3onGPCKnXLW64Ubox_XMrGm0UPqEnCHeMMaM6uxTciK15NYYfkp-XiQ3HTEinQMtI1Dv1sEVoGn1E6xIS3YJfY5LmQ9AY6priN_jsLoJ6W0sI0U_xh_zMmZI0dEx7sepVkEKIYAv98kulbjg0Y9ziR5rO9AEtzRH_Er3kACfkSehJsLzh_2cfHn_7vPlVXP96cPHy4vrxrfclqYLbnDWw6C98swpUFKHQYZgOTNO8Hbn3NBZ5uxOtaA6uTMtD1xqbXiQwstz8nrLXfL8bQUs_SGih2lyCeYVe2Ekb4U1oqvoq3_Qm3nN9bs2SgqmjKmU2CifZ8QMoV9yPLh87Dnr7zT1m6a-aurvNfV3Qy8fotfdAYY_I7-9VEBuANartIf89-3_xP4CrOqgsg</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Benjamin, Kynon J. 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M.</au><aucorp>BrainSeq Consortium</aucorp><aucorp>the BrainSeq Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes</atitle><jtitle>Nature neuroscience</jtitle><stitle>Nat Neurosci</stitle><addtitle>Nat Neurosci</addtitle><date>2022-11-01</date><risdate>2022</risdate><volume>25</volume><issue>11</issue><spage>1559</spage><epage>1568</epage><pages>1559-1568</pages><issn>1097-6256</issn><issn>1546-1726</issn><eissn>1546-1726</eissn><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. 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These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.
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DRD2
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| recordid | cdi_proquest_miscellaneous_2731429728 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| 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 |
| title | Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T23%3A07%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Analysis%20of%20the%20caudate%20nucleus%20transcriptome%20in%20individuals%20with%20schizophrenia%20highlights%20effects%20of%20antipsychotics%20and%20new%20risk%20genes&rft.jtitle=Nature%20neuroscience&rft.au=Benjamin,%20Kynon%20J.%20M.&rft.aucorp=BrainSeq%20Consortium&rft.date=2022-11-01&rft.volume=25&rft.issue=11&rft.spage=1559&rft.epage=1568&rft.pages=1559-1568&rft.issn=1097-6256&rft.eissn=1546-1726&rft_id=info:doi/10.1038/s41593-022-01182-7&rft_dat=%3Cproquest_cross%3E2731429728%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2731320577&rft_id=info:pmid/36319771&rfr_iscdi=true |