Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

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.

Genetic and Epigenetic Markers of Lithium Response

“…Recent studies that leveraged the GWAS dataset from the ConLiGen consortium as well as larger datasets on severe psychiatric disorders from the Psychiatric Genomics Consortium, suggested a high genetic load for schizophrenia (OR for lithium response ranging from 3.46 at the first decile to 2.03 at the ninth decile, compared with the patients in the 10th decile of schizophrenia risk) [66], major depressive disorder (lowest vs highest PRS quartiles OR = 1.54) [67] or attention deficit hyperactivity disorder (β = −0.14; p = 0.01) [68] to be associated with poor lithium response. In addition, a PRS combining variants associated with either schizophrenia or depression was recently shown to be able to improve the prediction of lithium response compared to single disorder PRS (proportion of phenotype variance explained by combined PRS: partial R 2 = 0.91%; schizophrenia-PRS: partial R 2 = 0.82%; depression-PRS partial R 2 = 0.47%) [69]. In the ConLiGen cohort, patients in the highest decile for the combined PRS had 2.5 times higher odds of being poor responders compared with patients in the lowest decile [69].…”

“…In addition, a PRS combining variants associated with either schizophrenia or depression was recently shown to be able to improve the prediction of lithium response compared to single disorder PRS (proportion of phenotype variance explained by combined PRS: partial R 2 = 0.91%; schizophrenia-PRS: partial R 2 = 0.82%; depression-PRS partial R 2 = 0.47%) [69]. In the ConLiGen cohort, patients in the highest decile for the combined PRS had 2.5 times higher odds of being poor responders compared with patients in the lowest decile [69]. These approaches are based on pleiotropy, i.e., a condition in which the same gene affects multiple phenotypes simultaneously.…”

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder

“…Genetic factors are thought to contribute, at least in part, to the large interindividual differences in response to lithium [10][11][12][13][14][15] . So far, only a few genetic studies have identi ed speci c single nucleotide polymorphisms (SNPs) and candidate genes associated with patients' response to lithium or treatmentrelated side effects 10,11,[13][14][15][16] .…”

“…Genetic factors are thought to contribute, at least in part, to the large interindividual differences in response to lithium [10][11][12][13][14][15] . So far, only a few genetic studies have identi ed speci c single nucleotide polymorphisms (SNPs) and candidate genes associated with patients' response to lithium or treatmentrelated side effects 10,11,[13][14][15][16] . Each employing a genome-wide association study (GWAS) approach, the Taiwan Bipolar Consortium found SNPs in the introns of GADL1 associated with lithium treatment response 17 , whereas the International Consortium on Lithium Genetics (ConLi + Gen) identi ed a locus on chromosome 21 10 , and a follow-up analysis uncovered additional variants within the human leukocyte antigen (HLA) region 14,16 .…”

“…In our recent work, we applied a polygenic score (PGS) modeling approach and demonstrated associations between a poor response to lithium and a high genetic loading for schizophrenia (SCZ) 14 , major depression (MD) 13 , and a meta-PGS combining both SCZ and MD 15 . Machine-learning models that combined clinical variables with the PGS of SCZ and MD has further improved the prediction of lithium treatment response, explaining 13.7% of the variance 19 .…”