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

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.

Dopamine and schizophrenia from bench to bedside: Discovery of a striatal co-expression risk gene set that predicts in vivo measures of striatal function

“…Genotype data for all samples were obtained and processed as previously described 92,93 . Genotype imputation and quality checks as well as calculation of genomic eigenvariates (GEs) for population stratification were performed in each cohort separately.…”

“…To identify SCZ-associated components more likely linked to pathogenic biology rather than treatment history or other factors, we additionally tested these components across samples for association with SCZ genetic risk before proceeding with further analyses. Only the SDA component C80 was also significantly associated with SCZ polygenic risk score (PRS), a measure of overall cumulative risk burden, in a diagnosisconsistent direction (see Online methods for PRS computation; C80: t [93]=1.67, one-tailed p=.048; C109: t[93]=-1.2, one-tailed p=.11) (Fig. 2a).…”

Consensus molecular environment of schizophrenia risk genes in coexpression networks shifting across age and brain regions

“…Notably, our results based on a connectivity match between networks across brain regions and age failed to support previous findings of less connected coexpression networks in the DLPFC of patients with SCZ (5). We hypothesize that the networks available with the present work may afford greater explanatory power in the translation of postmortem brain insights into neuroscience and clinical predictions in living patients with the latest available approaches (13)(14)(15)(53)(54)(55)(56)(57)(58)(59)(60).…”

Transcriptomics and proteomics of projection neurons in a circuit linking hippocampus with dorsolateral prefrontal cortex in human brain

“…These insights from bulk tissue data have been further translated into potential pathophysiological mechanisms of SCZ at gene 6,[9][10][11][12][13][14][15][16][17] , transcript 4,8,15 , and most recently, protein levels 18 .…”