Page 83 - GPD-4-3

Gene & Protein in Disease

ORIGINAL RESEARCH ARTICLE
Pre-addiction phenotype is associated

with dopaminergic dysfunction: Evidence
from 88.8 million genome-wide association
study-based samples

Kenneth Blum 1,2,3,4,5,6,7,8,9,10,11,12,13 * , Alireza Sharafshah 14 , Kai-Uwe
Lewandrowski 12,13,15,16 , Sérgio Luís Schmidt 13 , Rossano Kepler Alvim
Fiorelli , Albert Pinhasov 1 , Abdalla Bowirrat 1 , Mark S. Gold 17 , Eliot L.
13
18
Gardner , Panayotis K. Thanos 1,19 , Brian Fuehrlein 20 , David Baron 2,21 , Igor
Elman 1,22 , Catherine A. Dennen 23 , Nicole Jafari 9,24 , Foojan Zeine 10,25 ,
26
Alexander P.L. Lewandrowski , Milan Makale 27 , Edward J. Modestino 28 ,
Keerthy Sunder 2,7,29 , Kevin T. Murphy , Chynna Fliegelman , Shaurya
5
30
Mahajan 3,7 , Yatharth Mahajan , and Rajendra D. Badgaiyan 31
3
A list of affiliations appears at the end of the papers
Abstract
The convergence of neurogenetics, epigenetics, and functional neuroimaging
*Corresponding author: presented in this article marks a critical inflection point in our understanding and
Kenneth Blum management of reward deficiency syndrome (RDS) and its behavioral expressions
(drd2gene@gmail.com)
across pain and addiction medicine. The evidence for a hypodopaminergic state, now
Citation: Blum K, Sharafshah A, supported by decades of molecular, clinical, and imaging data, has culminated in the
Lewandrowski K, et al. Pre- formulation of a scientifically grounded, personalized, and preventative paradigm—
addiction phenotype is associated
with dopaminergic dysfunction: anchored by the concept of early genetic testing to provide risk information linked
Evidence from 88.8 million genome- to “prediction” predominantly due to dopaminergic dysfunction. From a translational
wide association study-based standpoint, this model offers more than a framework for understanding neurobiological
samples. Gene Protein Dis.
2025;4(3):8090. vulnerability; it provides a practical roadmap for early identification of “pre-addiction,”
doi: 10.36922/gpd.8090 informed opioid prescribing, relapse prevention, and long-term neurorecovery. The
coupling of Genetic Addiction Risk Severity (GARS) with dopaminergic modulation—
Received: December 20, 2024
via safe, non-addictive interventions—could redefine standard treatment algorithms
1st revised: March 19, 2025 not only for substance use disorders but also for a broader spectrum of compulsive
2nd revised: March 26, 2025 and comorbid behaviors. This study by members of the RDS Consortium explores the
concept of “pre-addiction” within addiction biology through a comprehensive in silico
3rd revised: April 16, 2025 analysis of 88,788,381 genome-wide association study-based samples from 1,373
4th revised: May 6, 2025 studies, identifying 18 significant genes (e.g., APOE with p=1.0E-126) linked to opioids,
pain, aging, and apoptosis pathways. It aims to correlate these genes with GARS,
Accepted: May 6, 2025
which includes 10 specific genes, and highlights the most connected genes, such as
Published online: July 3, 2025 MAOA, COMT, APOE, and SLC4A6, through a STRING model. The analysis expanded to
27 unique genes, emphasizing significant interactions with hsa-miR-16-5p and hsa-
Copyright: © 2025 Author(s).
This is an Open-Access article miR-24-3p, especially SLC6A4. Through pharmacogenomics mining, 1,173 variant
distributed under the terms of the annotations were identified for these genes. Enrichment analysis and meta-analysis
Creative Commons Attribution further validated these findings, illustrating the pivotal role of dopaminergic pathways
License, permitting distribution,
and reproduction in any medium, in connecting addictive behaviors and depressive symptoms. The results support the
provided the original work is conceptualization of RDS as the fundamental preaddiction phenotype, with pain,
properly cited. opioid dependence, aging, and apoptosis as critical endophenotypes.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Pre-addiction; Genetic addiction risk severity; Dopaminergic pathways;
regard to jurisdictional claims in
published maps and institutional Reward deficiency syndrome; APOE; Opioid dependence; Aging; Apoptosis
affiliations.

Volume 4 Issue 3 (2025) 1 doi: 10.36922/gpd.8090