Person-level contributions of bipolar polygenic risk score to the prediction of new-onset bipolar disorder in at-risk offspring
Danella Hafeman, Rudolf Uher, John Merranko, Alyson Zwicker, Benjamin I. Goldstein, Tina R. Goldstein, David Axelson, Kelly Monk, Dara Sakolsky, Satish Iyengar, Rasim Somer Diler, Vishwajit L. Nimgaonkar, Boris Birmaher
Abstract
Previous work indicates that polygenic risk scores (PRS) for bipolar disorder (BD) are elevated in adults and youth with BD, but whether BD-PRS can inform person-level diagnostic prediction is unknown. Here, we test whether BD-PRS improves performance of a previously published risk calculator (RC) for BD. 156 parents with BD-I/II and their offspring ages 6–18 were recruited and evaluated with standardized diagnostic assessments every two years for >12 years. DNA was extracted from saliva samples, genotyping performed, and BD-PRS calculated based on a 2021 meta-analysis. Using a bootstrapped and cross-validated penalized Cox regression, we assessed whether BD-PRS (alone and interacting with clinical variables) improved RC performance. Of 227 offspring, 38 developed BD during follow-up. The penalized regression selected BD-PRS and interactions between BD-PRS and parental age at mood disorder onset (AAO), depression, and anxiety. The resulting RC discriminated offspring who developed BD (vs. those that did not) with good accuracy (AUC = 0.81); removing BD-PRS and its interaction terms was associated with a significant decrement to the AUC (decrement = 0.07, p = 0.039). Further exploration of selected interaction terms indicated that all were significant ( p -values<0.02), indicating that BD-PRS has a larger effect on the outcome in offspring with depression and anxiety, whose affected parent had a younger AAO. The addition of BD-PRS to clinical/demographic predictors in the RC significantly improved its accuracy. BD-PRS predicted BD on the person-level, particularly in offspring of parents with earlier AAO who already had symptoms of anxiety and depression at intake. • Polygenic risk score for BD is elevated in those with BD, but its contributions to person-level prediction are unknown. • We tested whether the addition of BD-PRS to a previously published risk calculator improves prediction. • The addition of BD-PRS to the risk calculator improved prediction accuracy, especially in symptomatic youth. • Although BD-PRS explains a limited amount of variance, it adds to clinical factors to improve person-level prediction.