Associations between polygenic risk for bipolar disorder and transition to bipolar disorder in first episode depression patients

Bipolar disorder (BD) is characterized by alternating episodes of depression and (hypo)mania, often resulting in an initial misdiagnosis of major depressive disorder (MDD) and hence delaying appropriate treatment for the patients. BD is highly heritable and BD polygenic risk scores (BD-PRS) based on the recent genome-wide association studies (GWAS) are shown to be robust indicators of individual genetic predisposition to BD, with higher BD-PRS being associated with increased odds of lifetime BD diagnosis. Therefore, BD-PRS may have potential utility in patient stratification of first episode depression patients to assess the risk of transitioning to BD. The aim of this study was to utilize large-scale electronic health record history and genomic data to test whether BD-PRS is associated with MDD transition to BD in a large population-based biobank. We used data from the Estonian Biobank (n =190,639), which is linked to the National Health Insurance Fund's database that contains data of all diagnoses and prescription bills for years 2004-2021. We identified 53,290 first episode depression cases (based on ICD-10 codes F32, F33, F41.2) of whom 785 later transitioned to BD (ICD-10 codes F30, F31). Logistic regression was used for association testing, adjusted for birth year, sex and 5 genetic principal components. In addition to BD-PRS, we also tested the associations with MDD-PRS and schizophrenia PRS (SCZ-PRS) as well as ran a mutually adjusted model to correct for genetic correlations between BD, MDD and SCZ. PRSs were computed based on results of the latest and largest PGC GWAS meta-analysis, using the PRS-CS algorithm and all PRSs were converted to z-scores prior analyses. One standard deviation (SD) increase in BD-PRS increased the odds of transitioning to BD by 27% (OR = 1.27; 95% CI=1.18-1.37). Although both, MDD-PRS and SCZ-PRS were also associated with the BD transition (18% and 16% for each SD increase in PRS, respectively), in the mutually adjusted model SCZ-PRS was no longer associated and MDD-PRS dropped to 10%, while BD-PRS only dropped slightly (from 27% to 24% per 1 SD change in PRS). The group in the highest BD-PRS decile showed 2.2 times higher odds of transitioning to BD compared to the lowest decile group (OR = 2.17; 95% CI=1.56-3.06). These results indicate that higher BD-PRS is associated with increased risk for MDD-to-BD transition in the first-episode depression patients. Polygenic prediction-based methods may be useful for patient stratification of first-episode depression in the future, however more research is needed to develop more precise prediction algorithms including other clinically relevant predictors.