THE EFFECT OF DOPAMINE RECEPTOR D1 (DRD1) GENE VARIANTS ON CHANGES IN CRAVING SEVERITY DURING ALCOHOL WITHDRAWAL

Abstract Background Alcohol dependence (AD) is a complex disorder with unclear underlying etiologies. One strategy to understand its pathophysiology involves investigating the behaviors or symptoms, namely subphenotypes, associated with AD. Given that aggression is a prevalent behavior in individuals with AD and is associated with a poor outcome, we attempted to examine the biological underpinnings of aggression as a subphenotype of AD in terms of genetic predisposition. Furthermore, we also explored the impact of genes on craving, a hallmark of AD and AD relapse. Aims & Objectives This study aimed to identify the association of aggression-related candidate genes with AD. In addition, we also investigated the genetic association with changes in craving severity following 2 weeks of alcohol withdrawal. Method A total of 210 treatment-seeking patients with AD and 117 healthy controls were recruited in this study. 7 candidate genes were screened based on genome-wide genotyping Axiom Genome-Wide TWB 2.0 Array, included MECOM, AVPR1A, DRD1, DRD2, DRD3, RBOX1, and HTR2A. We followed the Alcohol Craving Questionnaire-Short Form-Revised (ACQ-SF-R) and Obsessive-Compulsive Drinking Scale (OCDS), both of which were used to assess the severity of alcohol craving during withdrawal. Results Among the candidate genes, we identified a significant association of Dopamine Receptor D1 ( DRD1) gene with AD. The DRD1 single nucleotide polymorphisms (SNPs) (rs12518222, rs144667196, rs4867798, rs686, rs4532, rs5326, and rs265981) were further examined, and we found these SNPs were significantly associated with AD. The minor alleles of rs12518222, rs4867798, rs686, rs4532, rs5326, rs265981 were associated with higher craving scores throughout the withdrawal period. Haplotype-based analyses also demonstrated a significant association of DRD1 gene with less craving alleviation during alcohol withdrawal. Discussion & Conclusion Our data indicates an association between the aggression-related gene DRD1 and AD within Taiwanese population. Particularly, patients harboring the minor alleles of DRD1 SNPs have a higher risk of AD and display a higher post-withdrawal craving scores compared to those harboring their counterparts. These findings, indicating that DRD1 gene plays a role in the susceptibility to AD and retards craving amelioration during the recovery phase, suggest that aggression might intricately involve neurobiological mechanisms contributing to AD.