Content area
Background
The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic and mechanistic aspects of psychopathology. We used a multi-omics approach to examine how HiTOP’s psychopathology spectra (externalizing [EXT], internalizing [INT], and shared EXT + INT) map onto RDoC’s units of analysis.
Methods
We 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 psychopathology. Finally, we tested causal relationships between each spectrum and physical health conditions.
Results
Using 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. INT genetic liability showed stronger causal effects on physical health – including chronic pain and cardiovascular diseases – than EXT.
Conclusions
Our 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.
Details
Amygdala;
Analysis;
Magnetic resonance imaging;
Datasets;
Substantia grisea;
Genome-wide association studies;
γ-Aminobutyric acid;
Circuits;
Genomics;
Cortex;
Brain research;
Psychopathology;
Therapeutic targets;
Mental disorders;
Chronic illnesses;
Health status;
Genomes;
Chronic pain;
Genes;
Dopamine;
Gene loci;
Serotonin;
Brain;
Hippocampus;
Neurons;
Gene expression;
Classification;
Cardiovascular diseases;
Internalization;
Cardiovascular disease;
Frame analysis;
Mental health;
Physiology;
Neuroimaging;
Causality;
Drugs;
Genetics;
Therapy
; Khan, Yousef 2
; Toikumo, Sylvanus 1
; Jinwala, Zeal 2
; Boomsma, Dorret I 3
; Levey, Daniel F 4
; Gelernter, Joel 5
; Kember, Rachel L 1
; Kranzler, Henry R 1
1 Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA; Department of Psychiatry, Center for Studies of Addiction, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2 Department of Psychiatry, Center for Studies of Addiction, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
3 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, The Netherlands and Amsterdam Reproduction and Development Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
4 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Psychiatry Division, VA Connecticut Healthcare Center, West Haven, CT, USA
5 Psychiatry Division, VA Connecticut Healthcare Center, West Haven, CT, USA; Departments of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, New Haven, CT, USA