Transdiagnostic Polygenic Risk Models for Psychopathology and Comorbidity: Cross-Ancestry Analysis in the All of Us...

Area of Science:

• Psychiatric Genetics
• Computational Psychiatry
• Genomic Epidemiology

Background:

• Psychiatric disorders share significant genetic underpinnings.
• The efficacy of transdiagnostic genetic risk models remains under investigation.
• Current polygenic risk scores (PRSs) are often disorder-specific.

Purpose of the Study:

• To compare the predictive performance of common psychiatric genetic (CPG) factor-based PRSs against disorder-specific PRSs.
• To assess the utility of transdiagnostic PRSs for predicting individual psychiatric disorder risk and comorbidity burden.
• To evaluate the impact of ancestral diversity on PRS performance.

Main Methods:

• Utilized data from the All of Us Research Program (N=102,091).
• Developed and compared CPG factor-based PRSs with traditional disorder-specific PRSs.
• Assessed predictive performance across 11 psychiatric conditions and overall comorbidity.
• Conducted cross-ancestry analyses to examine population-specific performance.

Main Results:

• CPG PRSs significantly outperformed disorder-specific PRSs, explaining 1.07 to 24.6 times more phenotypic variance.
• Disorder-specific PRSs offered complementary, albeit smaller, contributions to genetic risk prediction.
• CPG PRSs demonstrated comparable or superior predictive performance for most disorders and comorbidity burden.
• European-centric genome-wide association study (GWAS) datasets showed limitations for non-European populations.

Conclusions:

• Transdiagnostic PRSs hold substantial potential for advancing psychiatric genetics research and clinical applications.
• Shared genetic factors captured by CPG PRSs are highly predictive of psychiatric disorder risk.
• Development of equitable, ancestrally diverse genetic risk models is crucial for accurate prediction across all populations.