Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk: a [18F]-DOPA PET study

Rogdaki, Maria, Devroye, Céline, Ciampoli, Mariasole, Veronese, Mattia, Ashok, Abhishekh H., McCutcheon, Robert A., Jauhar, Sameer, Bonoldi, Ilaria, Gudbrandsen, Maria, Daly, Eileen, van Amelsvoort, Therese, Van Den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Turkheimer, Federico, Papaleo, Francesco and Howes, Oliver D. 2023. Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk: a [18F]-DOPA PET study. Molecular Psychiatry 28 , pp. 1995-2006. 10.1038/s41380-021-01108-y

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Abstract

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Kicer. There was an inverse linear effect of copy number variant number on striatal Kicer value (B = −1.2 × 10−3, SE = 2 × 10−4, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Kicer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen’s d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen’s d = 2) groups. Moreover, Kicer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License. A Correction to this article was published on 22 June 2021 - https://doi.org/10.1038/s41380-021-01192-0.
Publisher:	Springer Nature
ISSN:	1359-4184
Date of First Compliant Deposit:	23 February 2022
Date of Acceptance:	8 April 2021
Last Modified:	28 Feb 2024 12:02
URI:	https://orca.cardiff.ac.uk/id/eprint/147767

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