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000269348 1001_ $$00000-0002-7940-0335$$aAmare, Azmeraw T$$b0
000269348 245__ $$aAssociation of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
000269348 260__ $$aLondon$$bMacmillan$$c2023
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000269348 520__ $$aLithium 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.
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000269348 650_7 $$09FN79X2M3F$$2NLM Chemicals$$aLithium
000269348 650_7 $$03KX376GY7L$$2NLM Chemicals$$aGlutamic Acid
000269348 650_7 $$2NLM Chemicals$$aLithium Compounds
000269348 650_7 $$0N9YNS0M02X$$2NLM Chemicals$$aAcetylcholine
000269348 650_7 $$2NLM Chemicals$$aAntimanic Agents
000269348 650_2 $$2MeSH$$aBipolar Disorder: drug therapy
000269348 650_2 $$2MeSH$$aBipolar Disorder: genetics
000269348 650_2 $$2MeSH$$aHumans
000269348 650_2 $$2MeSH$$aFemale
000269348 650_2 $$2MeSH$$aMale
000269348 650_2 $$2MeSH$$aMultifactorial Inheritance: genetics
000269348 650_2 $$2MeSH$$aAdult
000269348 650_2 $$2MeSH$$aMiddle Aged
000269348 650_2 $$2MeSH$$aLithium: therapeutic use
000269348 650_2 $$2MeSH$$aLithium: pharmacology
000269348 650_2 $$2MeSH$$aTreatment Outcome
000269348 650_2 $$2MeSH$$aBayes Theorem
000269348 650_2 $$2MeSH$$aGenome-Wide Association Study: methods
000269348 650_2 $$2MeSH$$aGlutamic Acid: metabolism
000269348 650_2 $$2MeSH$$aCohort Studies
000269348 650_2 $$2MeSH$$aLithium Compounds: therapeutic use
000269348 650_2 $$2MeSH$$aLithium Compounds: pharmacology
000269348 650_2 $$2MeSH$$aAcetylcholine: metabolism
000269348 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000269348 650_2 $$2MeSH$$aAntimanic Agents: therapeutic use
000269348 650_2 $$2MeSH$$aAntimanic Agents: pharmacology
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000269348 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-023-02149-1$$gVol. 28, no. 12, p. 5251 - 5261$$n12$$p5251 - 5261$$tMolecular psychiatry$$v28$$x1359-4184$$y2023
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