Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

Leonardo Sportelli, Daniel P. Eisenberg, Roberta Passiatore, Enrico D’Ambrosio, Linda A. Antonucci, Jasmine S. Bettina, Qiang Chen, Aaron L. Goldman, Michael D. Gregory, Kira Griffiths, Thomas M. Hyde, Joel E. Kleinman, Antonio F. Pardiñas, Madhur Parihar, Teresa Popolizio, Antonio Rampino, Joo Heon Shin, Mattia Veronese, William S. Ulrich, Caroline F. Zink, Alessandro Bertolino, Oliver D. Howes, Karen F. Berman, Daniel R. Weinberger () and Giulio Pergola ()
Additional contact information
Leonardo Sportelli: Johns Hopkins Medical Campus
Daniel P. Eisenberg: Intramural Research Program, NIH, DHHS
Roberta Passiatore: University of Bari Aldo Moro
Enrico D’Ambrosio: University of Bari Aldo Moro
Linda A. Antonucci: University of Bari Aldo Moro
Jasmine S. Bettina: Intramural Research Program, NIH, DHHS
Qiang Chen: Johns Hopkins Medical Campus
Aaron L. Goldman: Johns Hopkins Medical Campus
Michael D. Gregory: Intramural Research Program, NIH, DHHS
Kira Griffiths: King’s College London
Thomas M. Hyde: Johns Hopkins Medical Campus
Joel E. Kleinman: Johns Hopkins Medical Campus
Antonio F. Pardiñas: Cardiff University
Madhur Parihar: Johns Hopkins Medical Campus
Teresa Popolizio: IRCCS Ospedale Casa Sollievo della Sofferenza
Antonio Rampino: University of Bari Aldo Moro
Joo Heon Shin: Johns Hopkins Medical Campus
Mattia Veronese: University of Padua
William S. Ulrich: Johns Hopkins Medical Campus
Caroline F. Zink: Baltimore Research and Education Foundation
Alessandro Bertolino: University of Bari Aldo Moro
Oliver D. Howes: King’s College London
Karen F. Berman: Intramural Research Program, NIH, DHHS
Daniel R. Weinberger: Johns Hopkins Medical Campus
Giulio Pergola: Johns Hopkins Medical Campus

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia.

Date: 2024
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DOI: 10.1038/s41467-024-47456-5

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