A polygenic score indexing a DRD2 -related co-expression network is associated with striatal dopamine function

D’Ambrosio, Enrico, Pergola, Giulio, Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Dahoun, Tarik, Veronese, Mattia, Sportelli, Leonardo, Taurisano, Paolo, Griffiths, Kira, Jauhar, Sameer, Rogdaki, Maria, Bloomfield, Michael A. P., Froudist-Walsh, Sean, Bonoldi, Ilaria, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Blasi, Giuseppe, Bertolino, Alessandro and Howes, Oliver D. 2022. A polygenic score indexing a DRD2 -related co-expression network is associated with striatal dopamine function. Scientific Reports 12 (1) , 12610. 10.1038/s41598-022-16442-6

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Abstract

Abstract: The D2 dopamine receptor (D2R) is the primary site of the therapeutic action of antipsychotics and is involved in essential brain functions relevant to schizophrenia, such as attention, memory, motivation, and emotion processing. Moreover, the gene coding for D2R (DRD2) has been associated with schizophrenia at a genome-wide level. Recent studies have shown that a polygenic co-expression index (PCI) predicting the brain-specific expression of a network of genes co-expressed with DRD2 was associated with response to antipsychotics, brain function during working memory in patients with schizophrenia, and with the modulation of prefrontal cortex activity after pharmacological stimulation of D2 receptors. We aimed to investigate the relationship between the DRD2 gene network and in vivo striatal dopaminergic function, which is a phenotype robustly associated with psychosis and schizophrenia. To this aim, a sample of 92 healthy subjects underwent 18F-DOPA PET and was genotyped for genetic variations indexing the co-expression of the DRD2-related genetic network in order to calculate the PCI for each subject. The PCI was significantly associated with whole striatal dopamine synthesis capacity (p = 0.038). Exploratory analyses on the striatal subdivisions revealed a numerically larger effect size of the PCI on dopamine function for the associative striatum, although this was not significantly different than effects in other sub-divisions. These results are in line with a possible relationship between the DRD2-related co-expression network and schizophrenia and extend it by identifying a potential mechanism involving the regulation of dopamine synthesis. Future studies are needed to clarify the molecular mechanisms implicated in this relationship.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2045-2322
Date of First Compliant Deposit:	25 July 2022
Date of Acceptance:	11 July 2022
Last Modified:	10 May 2023 23:20
URI:	https://orca.cardiff.ac.uk/id/eprint/151450

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