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

Sportelli, Leonardo, Eisenberg, Daniel P., Passiatore, Roberta, D’Ambrosio, Enrico, Antonucci, Linda A., Bettina, Jasmine S., Chen, Qiang, Goldman, Aaron L., Gregory, Michael D., Griffiths, Kira, Hyde, Thomas M., Kleinman, Joel E., Pardiñas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Parihar, Madhur, Popolizio, Teresa, Rampino, Antonio, Shin, Joo Heon, Veronese, Mattia, Ulrich, William S., Zink, Caroline F., Bertolino, Alessandro, Howes, Oliver D., Berman, Karen F., Weinberger, Daniel R. and Pergola, Giulio 2024. Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo. Nature Communications 15 (1) , 3342. 10.1038/s41467-024-47456-5

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	1 May 2024
Date of Acceptance:	22 March 2024
Last Modified:	01 May 2024 09:31
URI:	https://orca.cardiff.ac.uk/id/eprint/168555

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