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

• 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
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-022-01182-7

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.