712. Comorbid mental and substance use disorders – the role of genetic susceptibility
Abstract Background Alcohol use disorder (AUD) and alcohol consumption (AC) are highly heritable, globally burdensome, and frequently comorbid with severe psychiatric disorders like schizophrenia (SCZ) and bipolar disorder (BD). While these comorbidities are often linked to greater illness severity, it remains unclear whether they arise solely as complications of substance use or from a shared underlying genetic architecture. Aims & Objectives The overall aim was to leverage massive, diverse datasets and novel statistical frameworks to: i) Identify novel genetic loci associated with a narrow AUD phenotype across multiple ancestries. ii) Characterize the shared genomic loci and polygenic overlap between alcohol traits (AUD/AC) and psychiatric phenotypes (SCZ/BD). iii) Map identified variants to biological pathways and brain regions to uncover potential drug targets. Method A multi-ancestry GWAS was conducted on 1,041,450 individuals (including European, African, Hispanic, and Asian ancestries) using novel statistical tools and cross-ancestry functional analyses. We also used European-ancestry summary statistics (AUD: 34,658 cases; AC: n=200,680; SCZ: 31,013 cases; BD: 20,352 cases), and applied conjunctional False Discovery Rate (conjFDR) analysis to increase the power to detect shared genomic loci. The identified loci were mapped to gene expression data in the brain and examined for enrichment in specific neuronal pathways (GABAergic, dopaminergic, serotonergic) and immune-related gene sets. Results The multi-ancestry analysis identified 37 genome-wide significant loci, including seven novel for AUD. The conjFDR analysis further identified 28 loci shared between SCZ and AUD, and 2 loci shared between BD and AUD, many of which were previously unknown for these phenotypes. Loci were mapped to genes with altered expression in the striatum, hypothalamus, and prefrontal cortex. While European and African samples showed distinct immune-related patterns, shared loci between AUD and psychiatric disorders exhibited a complex mixture of both same and opposite effect directions. Extensive positive genetic correlations and polygenic overlap were found between AUD and both mental and general medical phenotypes, confirming that AUD shares a significant genetic liability with these conditions. Discussion & Conclusions These findings underscore the value of multi-ancestry and cross-disorder genetic studies in SUD. By identifying shared and novel genomic loci, we demonstrates that the relationship between alcohol use and psychiatric disorders is driven by a complex, shared genetic architecture rather than environmental complications alone. This advances our understanding of AUD risk and highlights potential neuronal and immune pathways for future clinical intervention.