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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2023 Dec; Vol. 28 (12), pp. 5251-5261. Date of Electronic Publication: 2023 Jul 11. - Publication Year :
- 2023
-
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 <superscript>+</superscript> <subscript>PGS</subscript> ) 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 <superscript>+</superscript> <subscript>PGS</subscript> was developed in the International Consortium of Lithium Genetics cohort (ConLi <superscript>+</superscript> Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li <superscript>+</superscript> <subscript>PGS</subscript> 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 <superscript>+</superscript> <subscript>PGS</subscript> was positively associated with lithium treatment response in the ConLi <superscript>+</superscript> Gen cohort, in both the categorical (P = 9.8 × 10 <superscript>-</superscript> <superscript>12</superscript> , R <superscript>2</superscript> = 1.9%) and continuous (P = 6.4 × 10 <superscript>-</superscript> <superscript>9</superscript> , R <superscript>2</superscript> = 2.6%) outcomes. Compared to bipolar patients in the 1 <superscript>st</superscript> decile of the risk distribution, individuals in the 10 <superscript>th</superscript> 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 <superscript>-</superscript> <superscript>4</superscript> , R <superscript>2</superscript> = 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 <superscript>+</superscript> <subscript>PGS</subscript> may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Female
Male
Adult
Middle Aged
Treatment Outcome
Bayes Theorem
Genome-Wide Association Study methods
Glutamic Acid metabolism
Cohort Studies
Lithium Compounds therapeutic use
Lithium Compounds pharmacology
Acetylcholine metabolism
Polymorphism, Single Nucleotide genetics
Antimanic Agents therapeutic use
Antimanic Agents pharmacology
Bipolar Disorder drug therapy
Bipolar Disorder genetics
Multifactorial Inheritance genetics
Lithium therapeutic use
Lithium pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 28
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 37433967
- Full Text :
- https://doi.org/10.1038/s41380-023-02149-1