Abstract
Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
Highlights
Statistical analysis To assess the association of polygenic risk scores (PRS) of individual traits (SCZ, BD, and MD), the cross-disorder meta-summary PRSs of SCZ, MD and BD (MET3), an
Placing continuous shrinkage (CS) priors on SNP effect sizes for calculating PRS [42], we found that high genetic loadings for SCZ and MDD but not BD reduce patients’ likelihood of optimal clinical lithium response
We found that a combined PRS derived from GWAS meta-analysis of MDD and SCZ (MET2-PRS) improves genetic response prediction, compared forms of response to lithium are less well captured by SCZ, MDD, and BD (MET3)
Summary
Statistical analysis To assess the association of PRSs of individual traits (SCZ, BD, and MD), the cross-disorder meta-summary PRSs of SCZ, MD and BD (MET3), an. BD-PRS was not associated with Alda total MET2 genes, IPA® could unequivocally identify 256 genes in its (Supplementary Table 2). PRS beta values for all associations were database for enrichment and pathway analysis (Supplementary negative, indicating a consistent direction of effect of PRS for SCZ, Table 7).
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