Using multi-trait polygenic scores to predict lithium responsiveness in patients with bipolar disorder.

BACKGROUND: The predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder remains limited. AIMS: To enhance the prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and/or bipolar disorder aetiology. METHOD: We analysed data collected from bipolar disorder patients who had received lithium treatment for at least 6 months and participated in the International Consortium on Lithium Genetics study (N = 2367). The Alda scale was used to assess lithium responsiveness, and treatment outcome was defined as continuous total Alda score (0-10) and categorical outcome (favourable ≥7 versus unfavourable response). PGSs were calculated for 60 phenotypes grouped into 5 clinical-biological clusters: psychiatric and behavioural (#23 phenotypes), cardiometabolic (#17), autoimmune/inflammatory (#5), neurocognitive (#8) and renal function (#7). We applied cross-validated machine learning regression approaches in both outcomes within each cluster, with the selected features from each cluster subsequently combined to construct the final mt-PGS models. Model performance was assessed using explained variance (R2) for the continuous outcome, and both McFadden's pseudo-R2 and standard classification model parameters for the categorical outcome. RESULTS: mt-PGS explained between 5.70% (continuous outcome) and 9.11% (categorical outcome) of the interindividual variability in lithium responsiveness. Classification accuracy (area under the curve) for the categorical outcome was 68.24% (95% CI: 64.98-71.66), with a Brier score of 0.257. Of the 5 clusters, the PGSs for psychiatric and behavioural phenotypes were most strongly associated with lithium responsiveness, accounting for 3.67-6.52% of its variability. CONCLUSIONS: By integrating PGSs for multiple relevant phenotypes, predictive accuracy for lithium response improved substantially compared with single-trait methods. Future research incorporating larger, more diverse populations and combining genetic scores with clinical data holds promise for further enhancing prediction and advancing clinical implementation.