Dataset Information

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 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=2,367) 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<��.

SUBMITTER: Amare A

PROVIDER: S-EPMC9949170 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Amare Azmeraw A Thalamuthu Anbupalam A Schubert Klaus Oliver KO Fullerton Janice J Ahmed Muktar M Hartmann Simon S Papiol Sergi S Heilbronner Urs U Degenhardt Franziska F Tekola-Ayele Fasil F Hou Liping L Hsu Yi-Hsiang YH Shekhtman Tatyana T Adli Mazda M Akula Nirmala N Akiyama Kazufumi K Ardau Raffaella R Arias Bárbara B Aubry Jean-Michel JM Backlund Lena L Bhattacharjee Abesh Kumar AK Bellivier Frank F Benabarre Antoni A Bengesser Susanne S Biernacka Joanna J Birner Armin A Marie-Claire Cynthia C Cervantes Pablo P Chen Hsi-Chung HC Chillotti Caterina C Cichon Sven S Cruceanu Cristiana C Czerski Piotr P Dalkner Nina N Del Zompo Maria M DePaulo J Raymond JR Etain Bruno B Jamain Stéphane S Falkai Peter P Forstner Andreas J AJ Frisén Louise L Frye Mark M Gard Sébastien S Garnham Julie J Goes Fernando F Grigoroiu-Serbanescu Maria M Fallgatter Andreas A Stegmaier Sophia S Ethofer Thomas T Biere Silvia S Petrova Kristiyana K Schuster Ceylan C Adorjan Kristina K Budde Monika M Heilbronner Maria M Kalman Janos J Oraki Kohshour Mojtaba M Reich-Erkelenz Daniela D Schaupp Sabrina S Schulte Eva E Senner Fanny F Vogl Thomas T Anghelescu Ion-George IG Arolt Volker V Dannlowski Udo U Dietrich Detlef E DE Figge Christian C Jäger Markus M Lang Fabian F Juckel Georg G Spitzer Carsten C Reimer Jens J Schmauß Max M Schmitt Andrea A Konrad Carsten C von Hagen Martin M Wiltfang Jens J Zimmermann Jörg J Andlauer Till T Fischer Andre A Bermpohl Felix F Kraft Vivien V Matura Silke S Gryaznova Anna A Falkenberg Irina I Yildiz Cüneyt C Kircher Tilo T Schmidt Julia J Koch Marius M Gade Katrin K Trost Sarah S Haußleiter Ida I Lambert Martin M Rohenkohl Anja C AC Kraft Vivien V Grof Paul P Hashimoto Ryota R Hauser Joanna J Herms Stefan S Hoffmann Per P Jiménez Esther E Kahn Jean-Pierre JP Kassem Layla L Kuo Po-Hsiu PH Kato Tadafumi T Kelsoe John J Kittel-Schneider Sarah S Ferensztajn-Rochowiak Ewa E König Barbara B Kusumi Ichiro I Laje Gonzalo G Landén Mikael M Lavebratt Catharina C Leboyer Marion M Leckband Susan G SG Tortorella Alfonso A Manchia Mirko M Martinsson Lina L McCarthy Michael M McElroy Susan L SL Colom Francesc F Mitjans Marina M Mondimore Francis F Monteleone Palmiero P Nievergelt Caroline C Nöthen Markus M Novak Tomas T O'Donovan Claire C Ozaki Norio N Pfennig Andrea A Pisanu Claudia C Potash James J Reif Andreas A Reininghaus Eva E Rouleau Guy G Rybakowski Janusz K JK Schalling Martin M Schofield Peter P Schweizer Barbara W BW Severino Giovanni G Shilling Paul D PD Shimoda Kazutaka K Simhandl Christian C Slaney Claire C Squassina Alessio A Stamm Thomas T Stopkova Pavla P Maj Mario M Turecki Gustavo G Vieta Eduard E Veeh Julia J Witt Stephanie S Wright Adam A Zandi Peter P Mitchell Philip P Bauer Michael M Alda Martin M Rietschel Marcella M McMahon Francis F Schulze Thomas G TG Millischer Vincent V Clark Scott S Baune Bernhard B

Research square 20230214

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental 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 respo ...[more]

PMID: 36824922

Similar Datasets

Project description:Importance:Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). Objectives:To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. Design, Setting, and Participants:A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. Main Outcomes and Measures:Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. Results:Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. Conclusions and Relevance:This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Project description:ImportanceEstablishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth.ObjectiveTo evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD.Design, setting, and participantsThis community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021.ExposuresPRSs for BD, major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder.Main outcomes and measuresParticipants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies.ResultsA total of 156 parents with BD I/II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7 times during a mean (SD) of 13 (3.4) years of follow-up (84% retention). More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; P < .001) and depression (126 [50.2%] vs 52 [32.9%]; P < .001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio, 1.50; 95% CI, 1.19-1.89; P < .001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03-1.7; P = .02; explained 5.0% of the phenotypic variance). BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05-1.86; P = .02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86-14.62; P = .002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis. There were no significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder in parents or offspring and they were not significantly associated with BD onset.Conclusions and relevanceThe findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further developments occur.

Project description:Family and genetic studies indicate overlapping liability for major depressive disorder and bipolar disorder. The purpose of the present study was to determine whether this shared genetic liability influences clinical presentation.A polygenic risk score for bipolar disorder, derived from a large genome-wide association meta-analysis, was generated for each subject of European-American ancestry (n = 1,274) in the Sequential Treatment Alternatives to Relieve Depression study (STAR*D) outpatient major depressive disorder cohort. A hypothesis-driven approach was used to test for association between bipolar disorder risk score and features of depression associated with bipolar disorder in the literature. Follow-up analyses were performed in two additional cohorts.A generalized linear mixed model including seven features hypothesized to be associated with bipolar spectrum illness was significantly associated with bipolar polygenic risk score [F = 2.07, degrees of freedom (df) = 7, p = 0.04]. Features included early onset, suicide attempt, recurrent depression, atypical depression, subclinical mania, subclinical psychosis, and severity. Post-hoc univariate analyses demonstrated that the major contributors to this omnibus association were onset of illness at age ? 18 years [odds ratio (OR) = 1.2, p = 0.003], history of suicide attempt (OR = 1.21, p = 0.03), and presence of at least one manic symptom (OR = 1.16, p = 0.02). The maximal variance in these traits explained by polygenic score ranged from 0.8% to 1.1%. However, analyses in two replication cohorts testing a five-feature model did not support this association.Bipolar genetic loading appeared to be associated with bipolar-like presentation in major depressive disorder in the primary analysis. However, the results were at most inconclusive because of lack of replication. Replication efforts were challenged by different ascertainment and assessment strategies in the different cohorts. The methodological approach described here may prove useful in applying genetic data to clarify psychiatric nosology in future studies.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets