TY - JOUR
T1 - Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes
AU - The BrainSeq Consortium
AU - Benjamin, Kynon J.M.
AU - Chen, Qiang
AU - Jaffe, Andrew E.
AU - Stolz, Joshua M.
AU - Collado-Torres, Leonardo
AU - Huuki-Myers, Louise A.
AU - Burke, Emily E.
AU - Arora, Ria
AU - Feltrin, Arthur S.
AU - Barbosa, André Rocha
AU - Radulescu, Eugenia
AU - Pergola, Giulio
AU - Shin, Joo Heon
AU - Ulrich, William S.
AU - Deep-Soboslay, Amy
AU - Tao, Ran
AU - Matsumoto, Mitsuyuki
AU - Saito, Takeshi
AU - Tajinda, Katsunori
AU - Hoeppner, Daniel J.
AU - Collier, David A.
AU - Malki, Karim
AU - Miller, Bradley B.
AU - Furey, Maura
AU - Hibar, Derrek
AU - Kolb, Hartmuth
AU - Didriksen, Michael
AU - Folkersen, Lasse
AU - Kam-Thong, Tony
AU - Malhotra, Dheeraj
AU - Shin, Joo Heon
AU - Jaffe, Andrew E.
AU - Narurkar, Rujuta
AU - Straub, Richard E.
AU - Hyde, Thomas M.
AU - Kleinman, Joel E.
AU - Weinberger, Daniel R.
AU - Hyde, Thomas M.
AU - Kleinman, Joel E.
AU - Erwin, Jennifer A.
AU - Weinberger, Daniel R.
AU - Paquola, Apuã C.M.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85141140241&partnerID=8YFLogxK
U2 - 10.1038/s41593-022-01182-7
DO - 10.1038/s41593-022-01182-7
M3 - Article
C2 - 36319771
AN - SCOPUS:85141140241
SN - 1097-6256
VL - 25
SP - 1559
EP - 1568
JO - Nature neuroscience
JF - Nature neuroscience
IS - 11
ER -