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Gene & Protein in Disease Dopaminergic dysfunction as pre-addiction

Figure 5. Bar chart heatmap of the top 100 Gene Ontology across many studies, with dopamine metabolic process as the main process among
pharmacogenomics-filtered candidate genes
Abbreviations: ADHD: Attention deficit hyperactivity disorder; ASD: Autism spectrum disorder; SNP: Single-nucleotide polymorphism.

namely, hypodopaminergia in the mesolimbic brain of KOP (oprk1) and dynorphin (PDYN) in several brain
reward circuitry. 28,31,35 This dysfunction extends beyond regions. Moreover, other data also supports altered
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dopaminergic pathways to include disturbances in mu-opioid receptor functionality in rats prenatally exposed
opioidergic, serotonergic, cannabinergic, GABAergic, to VPA, which may underlie the social deficits observed as
glutamatergic, and cholinergic systems. These a function of opioid-valproic interaction. 71
dysregulations contribute to a clinical constellation known All phases of enrichment analysis confirmed the
as RDS—a failure of neurological homeostasis. 65 highly significant impacts of dopaminergic pathways and
In the current study, we performed a deep in silico depression phenotypes in the identified gene list. Antón-
PGx-based investigation of 50 candidate genes based on Galindo et al. recently explored the association of 275
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the GARS panel and the top-ranked genes involved in the dopaminergic genes and 176 serotonergic genes with
opioid, pain, aging, and apoptosis pathways. After PGx- these phenotypes by performing gene-based, gene-set,
based variant annotation filtering, a three-level analysis of and transcriptome-wide association studies in 11 GWAS
the refined genes was performed, which included primary datasets on SUD and related behaviors. They reported a
in silico, deep in silico, and deep meta-analyses. The meta- pleiotropic contribution of dopaminergic and serotonergic
analysis investigated PPIs, GMIs, TF-miRNA coregulatory genes to addiction and related behaviors, such as anxiety,
interactions, protein-drug interactions (PDIs), protein- irritability, neuroticism, and risk-taking behavior,
chemical interactions (PCIs), enrichment analyses, and highlighting a role for DA genes, which could explain,
clustering enrichment ontology. in part, the co-occurrence of these phenotypes. In terms
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The STRING analysis yielded a coherent network of 27 of depression, Kimbrel et al. analyzed a total of 633,778
pharmacogenomically annotated genes. GMI identified US military veterans having suicidal ideation. The top
three highly interconnected miRNAs, including hsa- single-nucleotide variants were largely intronic; five were
miR-16-5p, hsa-mIR-24-3p, and hsa-miR-146a-5p. Other independently replicated, including rs6557168 in ESR1,
articles in the literature highlight the importance of rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in
interconnected miRNAs in the addiction process. 66-68 PDIs DCC, and rs36006172 in TRAF3. These results reinforce
highlighted the notable role of SLC6A4 (5HTTLPR)—a the relevance of DRD2, ESR1, DCC, and TRAF3—genes
variable number of tandem repeat polymorphism mapped also featured in our dataset—as cross-ancestry risk markers
to the 5’ region of the serotonin transporter protein gene, for suicidal thoughts and behaviors.
one of the most studied variants concerning psychiatric Furthermore, CEO further emphasized behavioral
traits and measured by GARS. PCIs singled out valproic phenotypes and midbrain-associated neurotypes,
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acid (VPA) as the most interactive substance associated especially in the context of cell type-specific expression
with genes from all five hypothesized pathways, consistent profiles. A particularly relevant avenue of investigation
with evidence that valproate alters opioid-receptor involved the secretome of bone marrow stem cells
signaling. For example, the kappa opioid receptor (KOP) (BMSCSec), assessed in conditioned place preference
system modulates social response. Prenatal exposure to animal models and cerebral organoids (CeO) derived from
the antiepileptic and mood stabilizer VPA is associated Centralinduced pluripotent stem cells. These systems were
with impaired social response and altered gene expression used to evaluate the secretome’s antinociceptive properties

Volume 4 Issue 3 (2025) 7 doi: 10.36922/gpd.8090