“TO BE OR NOT TO BE” GWAS Ends the Controversy about the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS)

Abstract

Kenneth Blum,1– 5 Panayotis K Thanos,6 Colin Hanna,6 Mark S Gold,7 David Baron,2 Igor Elman8 1Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel; 2Division of Addiction Research & Education, Center for Exercise Sports, Mental Health, Western University Health Sciences, Pomona, CA, USA; 3Institute of Psychology, Eötvös Loránd University Budapest, Budapest, Hungary; 4Department of Psychiatry, Boonshoft School of Medicine, Wright University, Dayton, OH, USA; 5Department of Psychiatry, Human Integrated Services Unit, University of Vermont Center for Clinical & Translational Science, College of Medicine, Burlington, VT, USA; 6Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA; 7Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; 8Department of Psychiatry, Harvard University College of Medicine, Cambridge, MA, USACorrespondence: Kenneth Blum, Email [email protected]: Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.Keywords: GWAS, candidate genes, DRD2 gene, polymorphisms, hypodopaminergia, reward deficiency, addictive and non-addictive behaviors

Keywords

• gwas
• candidate genes
• drd2 gene
• polymorphisms
• hypodopaminergia
• reward deficiency
• and addictive and non-addictive behaviors.