Pleiotropic genetic architecture linking schizophrenia and substance use disorders

Schizophrenia (SCZ) frequently co-occurs with substance use disorders (SUDs), yet the genetic basis of this comorbidity remains unclear. Using the latest European-ancestry genome-wide association studies (GWAS) for SCZ, cannabis use disorder (CanUD), opioid use disorder (OUD), problematic alcohol use (PAU), tobacco use disorder (TUD), and a general addiction factor (AF), together with two SCZ and one SUD case-control samples with individual-level genotype data, we applied multiple complementary genomic approaches to characterize their shared genetic architecture. Significant positive genome-wide genetic correlations were observed across all SCZ-SUD pairs. Local genetic correlation analyses identified multiple genomic regions contributing to this shared architecture, with both positive and negative correlations, and evidence of genomic regions shared across multiple SCZ-SUD pairs. Polygenic overlap analyses indicated substantial sharing (25-50%) of trait-associated variants between SCZ and SUDs. Genomic structural equation modelling supported a common latent factor underlying SCZ and all SUDs, accounting for approximately 23% of SCZ variance. Cross-trait polygenic risk score (PRS) analyses showed bidirectional associations between SCZ and SUD genetic liability. Mendelian randomization analyses provided evidence for a bidirectional causal relationship between SCZ and CanUD. Horizontal pleiotropy analyses identified numerous loci with concordant and discordant effects across traits, including loci shared among multiple SCZ-SUD pairs. Gene mapping and enrichment analyses indicated pathways related to neuroplasticity, synaptic transmission, immune system, metabolism and proteolysis, including both shared and SCZ-SUD specific biological processes. Overall, these findings suggest that part of SCZ liability reflects genetic susceptibility to SUDs with potential implications for patient stratification and clinical management.