TY - JOUR
T1 - Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk
T2 - a [18F]-DOPA PET study
AU - Rogdaki, Maria
AU - Devroye, Céline
AU - Ciampoli, Mariasole
AU - Veronese, Mattia
AU - Ashok, Abhishekh
AU - McCutcheon, Robert A
AU - Jauhar, Sameer
AU - Bonoldi, Ilaria
AU - Gudbrandsen, Maria
AU - Daly, Eileen
AU - van Amelsvoort, Therese
AU - Van Den Bree, Marianne
AU - Owen, Michael J
AU - Turkheimer, Federico
AU - Papaleo, Francesco
AU - Howes, Oliver D
N1 - Funding Information:
Conflict of interest MR, CD, MC, AA, RAM, SJ, IB, MG, ED, TvA, FT and FP declare no competing interests. ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Astra-Zeneca, Autifony, Biogen, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither ODH nor his family has been employed by or has holdings/a financial stake in any biomedical company. MV is consultant for GSK but no competing interests with this work exists. MJO and MVDB report grants from Takeda Pharmaceuticals outside of the submitted work.
Funding Information:
Funding The clinical study was supported by Medical Research Council—UK (No. MC-A656-5QD30), Maudsley Charity (No. 666) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The above funding sources had no further role in study design; in the collection; analysis and interpretation of data; in the writing of the report; in the decision to submit the paper for publication. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. RAM is supported by the Wellcome Trust (Grant No. 200102/Z/15/Z) and the National Institute for Health Research. MV is supported by National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. TVA is funded by NIH 5U01MH101722-02; the International Consortium on Brain and Behaviour in 22q11 deletion syndrome; MVDB and MJO are supported by the Medical Research Council (MR/N022572/1 and MR/ L011166/1 and 2315/1), the National Institute for Mental Health (5UO1MH101724), Wellcome Trust StrategicAward (503147), Health & Care Research Wales (Welsh Government, 507556), Medical Research Council Centre grant (G0801418) and Medical Research Council Programme grant (G0800509). FP and CD have received funding from the Istituto Italiano di Tecnologia, the Brain and Behavior Research Foundation (2015 NARSAD Grant No. 23234), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 796244 (SOCIALBRAINCIRCUITS) and the MINDDS Action of the European COST Association.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/12
Y1 - 2021/5/12
N2 - 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 Ki
cer. There was an inverse linear effect of copy number variant number on striatal Ki
cer value (B = −1.2 × 10
−3, SE = 2 × 10
−4, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki
cer 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, Ki
cer 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.
AB - 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 Ki
cer. There was an inverse linear effect of copy number variant number on striatal Ki
cer value (B = −1.2 × 10
−3, SE = 2 × 10
−4, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki
cer 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, Ki
cer 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.
UR - http://www.scopus.com/inward/record.url?scp=85105785494&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01108-y
DO - 10.1038/s41380-021-01108-y
M3 - Article
C2 - 33981004
SN - 1359-4184
JO - Molecular Psychiatry
JF - Molecular Psychiatry
ER -