A GWAS Meta-meta-analysis and In-depth Silico Pharmacogenomic Investigations in Identification of APOE and Other Genes Associated with Pain, Anti-inflammatory, and Immunomodulating Agents in Opioid Use Disorder (OUD) Derived from 14.91 M Subjects

• Published in: Cellular and molecular neurobiology Vol. 45; no. 1; p. 76
• Main Authors: Sharafshah, Alireza, Motovali-bashi, Majid, Blum, Kenneth, Lewandrowski, Kai-Uwe, Gold, Mark S., Keshavarz, Parvaneh, Thanos, Panayotis K.
• Format: Journal Article
• Language: English
• Published: New York Springer US 31.07.2025; Springer Nature B.V
• Subjects: Alzheimer's disease; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apolipoprotein E; Apolipoproteins E - genetics; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cholesterol; Computer Simulation; Dopamine D2 receptors; Dopamine receptors; Drug abuse; Drug addiction; Drug dependence; Epigenetics; Genome-wide association studies; Genome-Wide Association Study - methods; High density lipoprotein; Humans; Immune system; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Immunosuppressive agents; Inflammation; Lipid metabolism; miRNA; Narcotics; Neurobiology; Neurodegenerative diseases; Neurological diseases; Neurosciences; Opioid-Related Disorders - drug therapy; Opioid-Related Disorders - genetics; Opioids; Original Research; Pain; Pain - drug therapy; Pain - genetics; Pharmacogenetics - methods; Pharmacogenomics; Phenotypes; Protein interaction; Proteins; Substance use disorder; Lipids; Pain; GWAS; APOE; Meta-meta-analysis; Opioids
• ISSN: 1573-6830; 0272-4340; 1573-6830
• DOI: 10.1007/s10571-025-01587-5

This study aimed to integrate genome-wide association studies (GWAS) with pharmacogenomics data to develop personalized pain and inflammatory therapeutics. Despite recent developments in the clinical utilities of pharmacogenomics, it needs more investigations for uncovering the complicated mechanisms of drugs from a genetic standpoint. The research addresses the increasing misuse of opioids during recovery, emphasizing personalized interventions for opioid use disorder (OUD). Key pain-related pathways were analyzed to uncover their interactions. Five GWAS traits, including pain, inflammatory biomarkers, immune system abnormalities, and opioid-related traits, were examined. Candidate genes extracted from GWAS datasets were refined through in silico analyses, including protein–protein interactions (PPIs), TF-miRNA coregulatory interactions, enrichment analysis (EA), and clustering enrichment analysis (CEA). A network of 50 highly connected genes was identified, with APOE emerging as a top candidate due to its role in cholesterol metabolism and opioid-induced lipid effects. Pharmacogenomics analysis highlighted significant gene annotations, including OPRM1, DRD2, APOE, GRIN2B, and GPR98, linking them to opioid dependence, neurological disorders, and lipid traits. Protein interaction analyses further validated these connections, with implications for epigenetic repair. Our findings reveal a strong association between APOE , opioid use, and Alzheimer’s disease, suggesting potential for novel recovery strategies. Combining HDL-boosting drugs with pro-dopaminergic regulators like KB220 may help prevent relapse. This study underscores the importance of integrating genetic and pharmacogenomic data to advance personalized therapies. Graphical Abstract This figure illustrates a perspective of our whole study starting with 5 GWAS ID datasets (Pain, Opioid Use Dependence (OUD), Opioid dependence, Inflammation, and Immunity), GWAS Meta-Meta analysis, in-depth silico and Pharmacogenomics (PGx) analyses leading to innovative findings. Obviously, the neuron cell reflects the main player of brain reward cascades and the three terminals of this neuron links to Alzheimer’s Disease (AD), Opioid Use (OU), and APOE as the main findings of this network-based investigation. The question mark in one of the pink circles refers to the other potential phenotypes which might be related to this map and suggest future studies to test this possibility.