Uncovering genetic mechanisms associated with harmful use of alcohol in admixed Latin Americans

Harmful use of alcohol (HUA) refers to drinking patterns that are associated with increased risk of medical complications and adverse social impacts. HUA is a multifactorial condition, involving neurotransmission system alterations, environmental factors, and genetic predisposition. Previous studies have identified numerous genetic variants associated with alcohol-related phenotypes. However, the generalizability of these findings remains limited, as most studies have primarily focused on European and Asian populations, leaving other ethnic groups, such as Latino Americans, underrepresented. Here, we explored the genetic mechanisms underlying HUA in admixed Brazilians. HUA was evaluated in 2,840 individuals using the Alcohol Use Disorder Identification Test (AUDIT). Genetic variations were assessed using a genome-wide genotyping array, followed by genotype imputation. Ancestry patterns were estimated by comparing individual variants with those of reference populations. Association analysis was performed using multivariate logistic regression, and the functional impacts of variants were investigated through in silico analysis. Pathway enrichment and network analyses were conducted to identify potential genetic mechanisms underlying HUA.

Ancestry analysis confirmed the admixed nature of the study population, with lower levels of European ancestry significantly associated (p < 0.05, Mann-Whitney U test) with increased risk of HUA, suggesting potential ancestry-related genetic or socio-environmental factors contributing to alcohol-related behaviors. The genome-wide association study identified a significant association between the variant rs1097611 at 1p33 and HUA p = 4.88 × 10^-8, odds ratio [OR] = 1.8, confidence interval [CI] = 1.46-2.23), based on a multivariate logistic regression model assuming additive genetic effects and adjusted for sex and European ancestry. The rs1097611 and other variants at this locus are located in regulatory regions and have been previously associated with differential CYP4B1 expression across multiple tissues. Other suggestive association signals (5 × 10^-8 < p < 10^- 5) were identified at loci previously implicated in addictive substance use behaviors, including alcohol and/or tobacco consumption, such as 10q21.2 (ARID5B), 5q34-q35.1 (SLIT3), and 10q11.23 (SGMS1). Genome-based pathway enrichment analysis revealed several mechanisms potentially involved in HUA, primarily related to neurobiological processes and neuronal signaling. Finally, network analysis revealed a highly interconnected cluster of nervous system-related pathways, pointing to their potential functional interplay.

This study identifies novel loci, particularly at 1p33 (CYP4B1), and genetic mechanisms potentially involved in HUA in an admixed Latin American population. Studies in diverse ethnic groups are crucial to uncover novel genetic risk variants for HUA and improve its management.