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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1559-1568 |
| Number of pages | 10 |
| Journal | Nature neuroscience |
| Volume | 25 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2022 |
Funding
For CommonMind DE and eQTL replication, we downloaded differential expression and eQTL results from Synapse ( https://www.synapse.org/ ), syn6183936 and syn4622659. For eQTL replication, we used caudate nucleus from GTEx v8, which is supported by the Common Fund of the Office of the Director of the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. We obtained eQTL data from the GTEx Portal ( https://gtexportal.org/home/datasets ). For variant–gene comparisons of eQTLs, we matched converted SNP IDs across datasets. We thank the Offices of the Chief Medical Examiner of Washington, DC, Northern Virginia, and Maryland for the provision of brain tissue used in this study. We also thank L.B. Bigelow and members of the LIBD Neuropathology Section for their work in assembling and curating the clinical and demographic information and organizing the Human Brain Tissue Repository of the Lieber Institute. Finally, we thank the families that have donated this tissue to advance our understanding of psychiatric disorders. This work is supported by the LIBD, the BrainSeq Consortium, the NIH T32 fellowship (T32MH015330) to K.J.M.B, NIH R01 (MH123183) to L.A.H and L.C.-T. and an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to J.A.E. We thank the Offices of the Chief Medical Examiner of Washington, DC, Northern Virginia, and Maryland for the provision of brain tissue used in this study. We also thank L.B. Bigelow and members of the LIBD Neuropathology Section for their work in assembling and curating the clinical and demographic information and organizing the Human Brain Tissue Repository of the Lieber Institute. Finally, we thank the families that have donated this tissue to advance our understanding of psychiatric disorders. This work is supported by the LIBD, the BrainSeq Consortium, the NIH T32 fellowship (T32MH015330) to K.J.M.B, NIH R01 (MH123183) to L.A.H and L.C.-T. and an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to J.A.E.
ASJC Scopus subject areas
- General Neuroscience