Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Abstract

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Exploring the genetics of lithium response in bipolar disorders

“…This procedure increased the number of markers and the quality of the dataset, increasing its suitability for polygenic score (PGS) analyses. Single nucleotide polymorphisms (SNPs) in 37 genes that were previously reported to contribute to Li response in ConLiGen following a gene-level genome-wide analysis (Amare et al 2023 ) were extracted from the dataset using a window of ± 1 kb from the start and end positions of the gene (according to the Ensembl hg19 genome build). Our final dataset contained 9374 SNPs corresponding to 34 Li response-linked genes and 2064 individuals with BP, from which 1669 had a diagnosis of BP-I and 370 of BP-II.…”

“…Moreover, genetic studies have established Li response as a polygenic trait (Papiol et al 2022 ). Previous work performed by the Consortium on Lithium Genetics (ConLiGen) has offered significant insights into the molecular mechanisms contributing to Li response (Amare et al 2023 ), as well as the links with the polygenic scores of other psychiatric disorders (Amare et al 2018 ; Schubert et al 2021 ; Coombes et al 2021 ) and with suicidal behavior (Yoshida et al 2019 ) in BP. However, the relationships between Li response and disease features, particularly comorbidity, remain largely unexplored.…”

Effectiveness of ultra-long-term lithium treatment: relevant factors and case series

“…The ConLiGen developed a polygenic score for lithium response and found its association with the Alda scale's categorical and continuous patterns. Furthermore, within this research, 36 candidate genes connected mostly with glutamatergic and cholinergic systems were revealed (Amare et al 2023). The ConLiGen group also studied an association of lithium response with Human Leukocyte Antigen (HLA) variants, showing that good response to lithium was associated with HLA-mediated low inflammation.…”

The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review

“…According to a recent systematic review, 59% (30/51) of all studies using polygenic scores in PGx have been conducted within the area of mental and behavioral diseases (Johnson et al, 2022). Some of the most notable of these studies have applied this approach to antidepressant (Li, Tian, Hinds, & Team, 2020; Pain et al, 2022), clozapine (Okhuijsen-Pfeifer et al, 2022; Pardiñas et al, 2023), and lithium (Amare et al, 2023) response but results are mixed and the variance explained by polygenic scores have been modest (e.g. <10%).…”