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Developing a Rat Model for Bipolar Disorder
Published on: May 2, 2025
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Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar
Nigussie T Sharew1,2, Scott R Clark1, Sergi Papiol3,4
1Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Biological Psychiatry Global Open Science
|August 18, 2025
Summary
Pathway-specific polygenic scores (PSPGSs) show promise for predicting lithium response in bipolar disorder. These scores offer biological insights and comparable predictive power to traditional genome-wide scores.
Area of Science:
- Psychiatric Genetics
- Pharmacogenomics
- Bipolar Disorder Research
Background:
- Polygenic scores (PGSs) can predict treatment response in psychiatry, but their biological basis is often unclear.
- Developing pathway-specific PGSs (PSPGSs) may improve biological interpretability for psychiatric treatment response.
- This study focuses on lithium response in bipolar disorder, a critical area for personalized medicine.
Purpose of the Study:
- To develop and evaluate pathway-specific polygenic scores (PSPGSs) for predicting lithium response in bipolar disorder patients.
- To assess the biological interpretability and predictive performance of PSPGSs compared to conventional PGSs.
- To identify specific biological pathways associated with lithium response.
Main Methods:
- Developed 9 pathway-specific PGSs (PSPGSs) using genes from lithium-affected pathways.
- Evaluated PSPGSs associations with lithium response (categorical and continuous) in a large cohort (ConLi+Gen, N=2367) and validated in two smaller cohorts.
- Used regression models, adjusting for confounders, with stringent statistical significance thresholds (p < .05 after multiple testing correction).
Main Results:
- PSPGSs for acetylcholine, GABA, and mitochondria were significantly associated with lithium response (categorical and continuous outcomes).
- PSPGSs for calcium channel, circadian rhythm, and GSK were associated with continuous lithium response.
- A combined PSPGS model explained up to 3.71% of the variance in lithium response, with acetylcholine variants showing a 3.03-fold increased likelihood of good response in the highest genetic loading group.
Conclusions:
- Pathway-specific PGSs (PSPGSs) demonstrate comparable predictive performance to genome-wide PGSs for lithium response.
- PSPGSs offer enhanced biological interpretability by utilizing a focused set of genetic variants.
- These findings support the potential of PSPGSs for personalized treatment selection in bipolar disorder.
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