Identification of potential therapeutic targets for problematic alcohol use using multi-omics data.

Background: Problematic alcohol use (PAU) is a serious global health issue with limited treatment options. Although genetic studies have identified genomic regions associated with PAU, the specific causal genes and proteins remain unclear. This study aimed to identify these causal genes by integrating diverse genetic and molecular data to inform better treatment strategies.

Methods: We used Mendelian randomisation (MR) to identify genes and proteins that may cause PAU by combining genetic data with gene activity in brain and blood tissues. Multiple statistical tests confirmed shared genetic signals between expression and PAU. We also examined their effects on other traits and potential interactions with existing drugs.

Findings: We identified 97 genes and 13 proteins that are likely to play a causal role in PAU through MR, with strong enrichment in brain tissues. These associations remained significant after Bonferroni correction and were further supported by colocalisation analyses (posterior probability of hypothesis 4 > 0.75) and consistency across multiple datasets. Some targets also showed concordant effects with PAU on other health outcomes, supported by Bonferroni-significant associations in phenome-wide analyses, suggesting potential for drug repurposing.

Interpretation: This study highlights molecular signatures in both brain and blood tissues that may contribute to the development of PAU. Integrative multi-omics analyses revealed shared biological pathways across neural and peripheral systems, suggesting the potential for developing multi-systemic interventions with favourable safety profiles.

Funding: This study was supported by Samsung Research Fund, Sungkyunkwan University, 2023.