Specificity of polygenic scores for psychiatric disorders beyond transdiagnostic genetic risk (p)
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Importance
Polygenic scores are increasingly used to estimate genetic liability for psychiatric disorders. However, their limited specificity to the disorders for which they are derived limits their clinical and research utility.
Objective
To determine whether associations between polygenic scores for major psychiatric disorders and psychopathology outcomes are primarily driven by transdiagnostic ( p ) or disorder-specific genetic risk.
Design
Cross-sectional study. Analyses were conducted from May 2024 to October 2024.
Setting
Population-based sample from the Twins Early Development Study.
Participants
Twins born in England and Wales between 1994 and 1996. Mental health data were collected from 2021 to 2023 when participants were aged 25 to 28 years. Participants with available genetic data and at least one quantitative symptom score included.
Main outcomes and measures
Quantitative symptom scores and self-reported psychiatric diagnoses. Associations were tested using generalized estimating equations for three types of polygenic scores: uncorrected polygenic scores; a transdiagnostic polygenic score indexing shared genetic variance across 11 psychiatric conditions ( p ); and residual disorder-specific scores corrected for p (non- p ).
Results
Analyses included between 5,789 and 6,546 (mean [SD] age, 26.4 [0.93] years; 7,244 [51.6%] female). The polygenic score for p consistently showed stronger associations with symptom scores than uncorrected polygenic scores, while associations with self-reported diagnoses were similar. Most uncorrected polygenic scores exhibited extensive cross-trait associations, which were substantially attenuated accounting for p , suggesting that much of the genetic signal captured by polygenic scores reflects transdiagnostic liability. Some non-p polygenic scores retained associations with their corresponding-traits, indicating residual specificity.
Conclusions and relevance
In this population-based sample of young adults, associations between polygenic scores and psychopathology outcomes primarily reflect transdiagnostic genetic risk, with limited evidence of disorder-specificity. Accounting for transdiagnostic genetic liability could improve the specificity and interpretability of polygenic scores.
Key Points
Question: To what extent do polygenic scores for psychiatric disorders reflect transdiagnostic (p) versus disorder-specific genetic risk across psychopathology?
Findings: In a UK population-based cohort of approximately 6,000 individuals, polygenic scores for psychiatric disorders were associated with both quantitative symptom scores and self-reported diagnoses largely due to the transdiagnostic p , with limited evidence of disorder-specificity.
Meaning: Accounting for transdiagnostic genetic risk could improve the specificity and interpretability of polygenic scores in psychiatric research and practice.
