Exploratory analysis of genetic variants in BDNF, GABA Receptors, and dopaminergic pathways with alcohol use disorder in a Spanish cohort

Abstract

[EN]Alcohol use disorder (AUD) is influenced by genetic factors that affect key neurobiological systems, including dopaminergic and GABAergic pathways, which regulate neurobehavioral functions and are modulated by brain-derived neurotrophic factor (BDNF). Variations in these genes contribute to individual vulnerability to AUD. In this study, we investigated single-nucleotide polymorphisms (SNPs) and haplotypic associations in GABRA1, GABRA2, and GABRA6, along with the dopaminergic pathway genes DRD2/ANKK1 and BDNF, in a Spanish cohort. Peripheral blood-derived genomic DNA was genotyped, and haplotype analyses were conducted. Individual SNPs in GABRA1, GABRA2, BDNF, and DRD2/ANKK1 showed no significant associations with AUD. In GABRA6, the rs3219151 T allele was more frequent in AUD patients than in controls (57.9% vs. 49.3%; p = 0.03), while the C allele appeared to show a potential protective association. In addition, the GAC haplotype of GABRA6 (rs2197414, rs1992647, rs3219151) was less frequent in AUD than in controls (0.071 vs. 0.122) and showed a protective association (OR = 0.58; 95% CI = 0.34-0.99; p = 0.045). Our findings provide exploratory evidence suggesting that specific genetic variants and haplotypes may contribute to AUD susceptibility and support the relevance of multigenic and haplotypic approaches for exploring the neurobiological mechanisms underlying AUD.