S. Aranda, D. Koller, S. Papiol, M. Soler Artigas, A. M. Perez-Gutierrez, J. Gonzalez-Penas, M. Budde, P. Jacome-Ferrer, C. Arango, K. Adorjan, E. Vilella, G. Muntane, L. Martorell, M. Heilbronner, M. D. Molto, O. Rivero, A. Navarro-Flores, J. Bobes, M. Oraki Kohshour, B. Crespo-Facorro, D. Reich-Erkelenz, A. Gonzalez-Pinto, E. C. Schulte, M. Arrojo, G. Florez, F. Senner, I.-G. Anghelescu, V. Arolt, D. E. Dietrich, A. J. Fallgatter, C. Figge, M. Jager, F. U. Lang, G. Juckel, C. Konrad, J. Reimer, E. Z. Reininghaus, M. SchmauB, A. Schmitt, C. Spitzer, Wil
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.