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Gene & Protein in Disease Dopaminergic dysfunction as pre-addiction

success of any meaningful reform to the current “standard 2. Methods
of care.” Interestingly, policies and possible governmental
regulations must adequately address drug manufacturing, 2.1. Genome-wide association study (GWAS)
trade, and prescribing practices, which are related to samples
a robust understanding of the mechanisms of both All relevant traits were obtained along with their
substance and nonsubstance addictive behaviors, referred corresponding Ontology ID. Each Ontology ID contained
3
to as the RDS. Moreover, it is no surprise that despite multiple studies, associations, and cumulative sample sizes.
improvements in the general practices of organizations We identified 19 traits for pain, opioid use, and aging,
globally, significant differences remain in the quality and 39 genes associated with apoptosis. Since apoptosis is
and quantity of the available treatment internationally a biological process rather than a trait, related genes were
amongst massive populations. 4 Notably, various included in the study instead. In total, 1,373 studies, 4,552
international organizations have made attempts to provide associations, and 88,788,381 samples were included as raw
up-to-date survey information related to many aspects of data (Table S1). Next, multiple filtering criteria were applied
both substance and nonsubstance behavioral addiction to the input data. Non-coding variants (intronic, intergenic,
practices. Despite these attempts to help identify ongoing and nonstructural RNA transcripts) were excluded, while
substance use and behavioral addictions like gambling missense and spicing variants representing proteomic and
and over-eating, there is no real reliable consensus as transcriptomic processes were retained. The remaining
to what constitutes these pathologies, which include variants were selected for their mapped genes. After
consideration of the neurogenetic and environmentally combining these mapped genes and removing duplicates,
induced alteration of DNA expression and the role of 219 genes remained. These genes were subsequently
microRNAs (miRNAs). Recently, the early identification analyzed for protein-protein interactions (PPIs) using a
5-7
of a “pre-addiction” state has begun to gain traction. STRING model.
8
Indeed, there has been significant advancement due to the 2.2. In silico and meta-analyses
mechanistic information garnered from neuroimaging
studies. However, arguably, these sophisticated studies The rationale for this novel strategy is based on our
9
are limited, especially as they relate to the complex array previously published work 52,53 and corroborated by
of 30,000 functional genes and even non-coding regions others. 54-59 We performed advanced PGx analyses to expand
in the human genome. A more comprehensive strategy the potential of the GARS panel (10 genes and 11 variants)
is needed to unravel the potential role of specific genes through a multi-model in silico investigation across
linked to reward deficiency, pain, aging, and apoptosis. multiple levels, including primary in silico, deep in silico,
and deep meta-analyses. The primary in silico assessments
Our overall goal in this study is to develop an approach were PPIs, followed by gene-miRNA interactions (GMIs).
to better understand pre-addiction. We hypothesize For deep in silico assessments, we investigated three major
that, through our novel PGx analysis, opioids—as potent ways of analyses, including pathway, Gene Ontology
analgesics—may not only contribute to addictive behavior (GO), and diseases-drug assessments (DDAs). To further
but also accelerate the aging process by inducing unwanted deepen the investigation, all enriched outcomes of the
apoptosis via mitochondria infractions. This cascade could in silico analyses were merged and reanalyzed through
subsequently lead to neurodegenerative disorders such as meta-analyses. Table S1 details all software tools and
Parkinson’s and Alzheimer’s disease. If supported by our databases employed in the current study, many of which
analysis, we aim to establish pre-addiction as the primary have been utilized in prior notable publications. Our raw
phenotype and aging as the endophenotype associated data incorporated previously documented GARS genes (10
with DA dysfunction. 1,10-47 An important rationale genes) along with genes related to opioid, pain, aging, and
for undertaking this massive analysis stems from the apoptosis pathways based on top-scored GWAS results
cautionary implications concerning “death by opioids.” involving 88 million samples (as of February 04, 2024).
48
We have previously suggested that chronic prescribing of For clarity, the analytic workflow is summarized in the
buprenorphine, methadone, and even morphine can lead flowchart displayed in Figure 2.
to unwanted premature death (e.g., suicide) 49,50 due to anti-
reward endophenotypes. These implications have been 3. Results
51
further substantiated by recent research. Specifically,
Fernandes et al. demonstrated that human central 3.1. GWAS-based samples
51
organoids (CEO) could be used as a model for investigating The GWAS catalog (https://www.ebi.ac.uk/gwas/
central pain mechanisms, such as opioid signaling pathways, home) was utilized as the main source of the input
and efficacy assessment of future therapeutics. data. This study followed a highly significant single-

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