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

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