Mapping unexplained genetic correlations across 14 psychiatric disorders

Abstract Background Transdiagnostic genetic factor models organize shared liability across psychiatric disorders, but they may leave systematic pairwise genetic overlap unexplained. Methods Using publicly available PGC cross-disorder LD score regression genetic correlations and published five-factor genomic SEM parameters, we computed model-implied disorder correlations and derived edge-level residual genetic correlations (observed minus model-implied) for all disorder pairs. We summarized residual misfit by ranking the largest residual edges and by aggregating residual edges into disorder-level hub indices. As a parsimonious comparison, we constructed a p-factor-augmented baseline and repeated the residual mapping. Uncertainty was propagated via Monte Carlo sampling using reported standard errors. Results Residual structure was concentrated in a subset of disorders rather than being uniformly distributed. The largest positive residual edge was OCD-anxiety (∼0.35), followed by prominent residual links including OCD-Tourette syndrome, ADHD-cannabis use disorder, and ASD-ADHD. At the node level, OCD emerged as the most consistent residual hub, with ADHD typically second. Under the p-factor baseline, the overall residual pattern persisted. Hub rankings did not map one-to-one onto disorder uniqueness, indicating complementary information captured by node-level and edge-level residuals. Conclusions Higher-order genetic factors explain broad shared liability but leave meaningful, structured residual links between specific disorder pairs. OCD and ADHD are robust residual hubs, highlighting candidate cross-disorder connections for targeted phenotypic harmonization, cross-phenotype GWAS, and theory-guided model refinements.