Integrating HiTOP and RDoC Frameworks Part II: Shared and Distinct Biological Mechanisms of Externalizing and Internalizing Psychopathology

Abstract

BackgroundThe Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic and mechanistic aspects of psychopathology, respectively. We used a multi-omics approach to examine how externalizing (EXT), internalizing (INT), and shared EXT+INT liability map onto these models. MethodsWe conducted analyses across five RDoC units of analysis: genes, molecules, cells, circuits, and physiology. Using genome-wide association studies from the companion Part I article, we identified genes and tissue-specific expression patterns. We used drug repurposing analyses that integrate gene annotations to identify potential therapeutic targets and single-cell RNA sequencing data to implicate brain cell types. We then used magnetic resonance imaging data to examine brain regions and circuits associated with each psychopathology spectrum. Finally, we tested causal relationships between each spectrum and physical health conditions. ResultsUsing five gene identification methods, EXT was associated with 1,759 genes, INT with 454 genes, and EXT+INT with 1,138 genes. Drug repurposing analyses identified potential therapeutic targets, including those that affect dopamine and serotonin pathways. Expression of EXT genes was enriched in GABAergic, cortical, and hippocampal neurons, while INT genes were more narrowly linked to GABAergic neurons. EXT+INT liability was associated with reduced gray matter volume in the amygdala and subcallosal cortex. Using Mendelian randomization, INT showed stronger causal effects on physical health--including chronic pain and cardiovascular diseases--than EXT. ConclusionsOur findings revealed shared and distinct pathways underlying psychopathology. Integrating genomic insights with the RDoC and HiTOP frameworks advanced our understanding of mechanisms that underlie EXT and INT psychopathology.