Relationship Between Problematic Alcohol Use and Various Psychiatric Disorders: A Genetically Informed Study.

OBJECTIVE Problematic alcohol use (PAU) adversely affects the clinical course of psychiatric disorders. Genetic studies have suggested that genetic factors underlie the co-occurrence of PAU with psychiatric disorders. This study aimed to elucidate shared genetic architectures, prioritizing genes that disorders may have in common. METHODS Using genome-wide association data of PAU including 435,563 samples from people of European ancestry, this study investigated the genetic relationship between PAU and 11 psychiatric disorders using a bivariate causal mixture model (MiXeR). Local genetic correlation and colocalization analyses were conducted to identify the genomic regions significantly associated with PAU and each psychiatric disorder. Postanalysis included the false discovery rate (FDR) and transcriptome-wide association studies (TWASs), as well as summary-data-based Mendelian randomization to prioritize shared genes by integrating brain transcriptome data. RESULTS MiXeR analysis revealed a substantial polygenic overlap (39%-73%) between PAU and psychiatric disorders. Four bivariate genomic regions with high correlations suggest shared causal variants of PAU with major depression and schizophrenia. Within these regions, four and six genes for the PAU-major depression and PAU-schizophrenia pairs, respectively, were mapped by conjunctional FDR analysis. Furthermore, TTC12 and ANKK1 were identified as potential causal genes for PAU and these disorders. The findings were replicated in multi-ancestry analyses of colocalization and TWASs. CONCLUSIONS Despite the varying degrees of genetic overlap and directions of shared genetic effect correlations, these results imply the presence of shared genetic factors influencing the comorbidity of PAU and psychiatric disorders. Additionally, TTC12 and ANKK1, located near DRD2, may be causally associated with comorbid conditions.