Genetic architecture of externalizing and internalizing traits in the general population and its link to psychiatric conditions and well-being: a multivariate approach

Externalizing and internalizing behaviours capture heritable, transdiagnostic dimensions of psychopathology, but their genetic architecture and links to societal outcomes remain incompletely understood. This study applied a multivariate framework to population-based, non-clinical traits to explore simultaneous genetic associations across externalizing and internalizing behaviours to elucidate their biological underpinnings and genetic relation to clinical diagnoses. Using genomic structural equation modelling, we built a two-factor model for externalizing (EXT) and internalizing (INT) behaviour utilizing 13 genome-wide association study (GWAS) summary statistics from population-based cohorts (n=64,000-1,200,000). We tested genetic correlations of EXT and INT with 12 psychiatric diagnoses (n=14,000-2,000,000) using linkage-disequilibrium score regression, and we studied genetic relation to emotional well-being with polygenic score analyses (PRS-CS) in an independent cohort (n= 4,565). Multivariate GWAS revealed 184 genome-wide significant loci for EXT and 31 for INT. Gene-level analyses identified 52 novel genes for EXT and 18 for INT. Enrichment analyses using single-cell-RNA-sequencing data showed significant enrichment in neuronal and non-neuronal populations, with strongest signals in hippocampal CA4 for EXT and amygdalar excitatory neurons for INT. EXT correlated with attention-deficit/hyperactivity disorder and substance-use disorders, INT showed significant genetic correlations with obsessive-compulsive disorder and anorexia nervosa. EXT and INT also exhibited overlap in genetic correlations with posttraumatic stress disorder, major depressive disorder, schizophrenia, and anxiety disorder. PRS-CS demonstrated association of INT liability with emotional well-being. Overall, these findings advance our understanding of the genetic architecture underlying transdiagnostic externalizing and internalizing behaviours and underscore their relevance for both psychiatric risk and emotional well-being.