Background: Lithium is a first-line medication for bipolar disorder (BD), but only ~30% of patients respond optimally to the drug. Since genetic factors are known to mediate lithium treatment response, we hypothesized whether polygenic susceptibility to the spectrum of depression traits is associated with treatment outcomes in patients with BD. In addition, we explored the potential molecular underpinnings of this relationship. Methods: Weighted polygenic scores (PGSs) were computed for major depressive disorder (MDD) and depressive symptoms (DS) in BD patients from the Consortium on Lithium Genetics (ConLi+Gen; n=2,586) who received lithium treatment. Lithium treatment outcome was assessed using the ALDA scale. Summary statistics from genome-wide association studies (GWAS) in MDD (130,664 cases and 330,470 controls) and DS (n=161,460) were used for PGS weighting. Associations between PGSs of depression traits and lithium treatment response were assessed by binary logistic regression. We also performed a cross-trait meta-GWAS, followed by Ingenuity Pathway Analysis. Outcomes: BD patients with a low polygenic load for depressive traits were more likely to respond well to lithium, compared to patients with high polygenic load (MDD: OR =1.64 [95%CI: 1.26-2.15], lowest vs highest PGS quartiles; DS: OR=1.53 [95%CI: 1.18-2.00]). Associations were significant for type 1, but not type 2 BD. Cross-trait GWAS and functional characterization implicated voltage-gated potassium channels, insulin-related pathways, mitogen-activated protein-kinase (MAPK) signaling, and miRNA expression. Interpretation: Genetic loading to depression traits in BD patients lower their odds of responding optimally to lithium. Our findings support the emerging concept of a lithium-responsive biotype in BD. Funding: see attached details. Keywords: lithium treatment, Major depressive disorder, depressive symptoms, depressive traits, bipolar disorder, polygenic score, pharmacogenomics, Voltage-gated potassium channel, insulin, MAPK.

Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder