Shared Genetic Architecture and Neurobiological Pathways of Problematic Alcohol Use and Anxiety Disorders.

Background: Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. Methods: We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Results: Mendelian randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation ( Conclusions: We found substantial genetic and neurobiological overlap of PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared underlying causal mechanisms linking the two conditions.