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Integrating HiTOP and RDoC Frameworks Part I: Genetic Architecture of Externalizing and Internalizing
Christal N Davis1,2, Yousef Khan2, Sylvanus Toikumo1,2
1Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
Medrxiv : the Preprint Server for Health Sciences
|April 22, 2024
Summary
Externalizing (EXT) and internalizing (INT) psychopathology share significant genetic links. Our study reveals substantial overlap in genetic variants, offering insights into the biological basis of these common mental health conditions.
Area of Science:
- Psychiatry
- Genetics
- Computational Biology
Background:
- Externalizing (EXT) and internalizing (INT) psychopathology frequently co-occur.
- Understanding shared genetic factors is vital for advancing biological insights and refining psychiatric classification systems like RDoC and HiTOP.
Purpose of the Study:
- To investigate the shared genetic architecture of externalizing and internalizing psychopathology.
- To identify genetic variants contributing to both spectra and their overlap.
Main Methods:
- Genomic structural equation modeling was applied to summary statistics from 16 EXT and INT traits.
- Multivariate genome-wide association studies (GWAS) were conducted on latent factors derived from the models.
Main Results:
- A two-factor correlated model best represented the genetic architecture of EXT and INT spectra.
- A moderate genetic correlation (r = 0.37) was observed between EXT and INT, with significant overlap in causal variants (94.64%).
- Multivariate GWAS identified numerous lead genetic variants for EXT, INT, and shared traits.
Conclusions:
- Shared genetic liabilities contribute to the high comorbidity of EXT and INT psychopathology.
- These findings provide a foundation for research into shared and distinct biological mechanisms.
- The results can inform psychiatric nosology and potential treatment strategies.
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