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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.
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1 King’s College London, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); University of Bari “Aldo Moro”, Department of Basic Medical Sciences, Neuroscience and Sense Organs, Bari, Italy (GRID:grid.7644.1) (ISNI:0000 0001 0120 3326)
2 University of Bari “Aldo Moro”, Department of Basic Medical Sciences, Neuroscience and Sense Organs, Bari, Italy (GRID:grid.7644.1) (ISNI:0000 0001 0120 3326); Lieber Institute for Brain Development, Baltimore, USA (GRID:grid.429552.d) (ISNI:0000 0004 5913 1291)
3 Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670)
4 King’s College London, Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
5 King’s College London, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); University of Padua, Department of Information Engineering, Padua, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470)
6 University of Bari “Aldo Moro”, Department of Basic Medical Sciences, Neuroscience and Sense Organs, Bari, Italy (GRID:grid.7644.1) (ISNI:0000 0001 0120 3326)
7 King’s College London, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
8 King’s College London, Centre for Affective Disorders, Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
9 University College London, Division of Psychiatry, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
10 New York University, Center for Neural Science, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753)
11 King’s College London, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); Imperial College London, Institute of Clinical Sciences (ICS), Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); H. Lundbeck A/S, Valby, Denmark (GRID:grid.424580.f) (ISNI:0000 0004 0476 7612)