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

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• dc.contributor.author Amare, Azmeraw T.
• dc.contributor.author Colom, Francesc
• dc.contributor.author Baune, Bernhard T.
• dc.date.accessioned 2024-05-28T06:23:02Z
• dc.date.available 2024-05-28T06:23:02Z
• dc.date.issued 2023
• dc.description.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.
• dc.description.sponsorship AT Amare received the 2019–2021 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Grant from the Brain & Behaviour Research Foundation (BBRF) and is currently supported by National Health and Medical Research Council (NHMRC) Emerging Leadership (EL1) Investigator Grant (APP2008000). The primary sources of funding were the Deutsche Forschungsgemeinschaft (DFG; grant no.RI 908/7-1; grant FOR2107, RI 908/11-1 to Marcella Rietschel, NO 246/10-1 to Markus M. Nöthen) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; ClinicalTrials.gov identifier: NCT00001174). The genotyping was in part funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grants awarded to Thomas G. Schulze, Marcella Rietschel, and Markus M. Nöthen). Improving Recognition and Care in Critical Areas of Bipolar Disorders (BipoLife) study was funded by Bundesministerium für Bildung und Forschung (BMBF): PIs – Felix Bermpohl, Philipp Ritter, Michael Bauer, Andreas Reif, Sarah Kittel-Schneider, Thomas G. Schulze, Jens Wiltfang, Georg Juckel, Andreas Fallgatter and Martin Lambert. Urs Heilbronner was supported by European Union’s Horizon 2020 Research and Innovation Programme (PSY-PGx, grant agreement No 945151). Some data and biomaterials were collected as part of eleven projects (Study 40) that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 2003–2007, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, M.D., Ph.D., Marvin J. Miller, M.D., Elizabeth S. Bowman, M.D., N. Leela Rau, M.D., P.Ryan Moe, M.D., Nalini Samavedy, M.D., Rif El-Mallakh, M.D. (at University of Louisville), Husseini Manji, M.D.(at Johnson and Johnson), Debra A.Glitz, M.D.(at Wayne State University), Eric T.Meyer, Ph.D., M.S.(at Oxford University, UK), Carrie Smiley, R.N., Tatiana Foroud, Ph.D., Leah Flury, M.S., Danielle M.Dick, Ph.D (at Virginia Commonwealth University), Howard Edenberg, Ph.D.; Washington University, St. Louis, MO, R01 MH059534, John Rice, Ph.D, Theodore Reich, M.D., Allison Goate, Ph.D., Laura Bierut, M.D.K02 DA21237; Johns Hopkins University, Baltimore, M.D., R01 MH59533, Melvin McInnis, M.D., J.Raymond DePaulo, Jr., M.D., Dean F. MacKinnon, M.D., Francis M. Mondimore, M.D., James B. Potash, M.D., Peter P. Zandi, Ph.D, Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini, M.D., Ph.D.; University of California at San Francisco, CA, R01 MH60068, William Byerley, M.D., and Sophia Vinogradov, M.D.; University of Iowa, IA, R01 MH059548, William Coryell, M.D., and Raymond Crowe, M.D.; University of Chicago, IL, R01 MH59535, Elliot Gershon, M.D., Judith Badner, Ph.D., Francis McMahon, M.D., Chunyu Liu, Ph.D., Alan Sanders, M.D., Maria Caserta, Steven Dinwiddie, M.D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, M.D., Rebecca McKinney, B.A.; Rush University, IL, R01 MH059556, William Scheftner, M.D., Howard M. Kravitz, D.O., M.P.H., Diana Marta, B.S., Annette Vaughn-Brown, M.S.N., R.N., and Laurie Bederow, M.A.; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J. McMahon, M.D., Layla Kassem, Psy.D., Sevilla Detera-Wadleigh, Ph.D, Lisa Austin, Ph.D, Dennis L. Murphy, M.D.; Howard University, William B. Lawson, M.D., Ph.D., Evarista Nwulia, M.D., and Maria Hipolito, M.D. This work was supported by the NIH grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by the Canadian Institutes of Health Research grant (#166098), as well as Genome Canada and Research Nova Scotia grants to MA. Collection and phenotyping of the Australian UNSW sample, by Philip B. Mitchell, Peter R. Schofield, Janice M. Fullerton and Adam Wright, was funded by an Australian NHMRC Program Grant (No.1037196). The collection of the Barcelona sample was supported by the Centro de Investigación en Red de Salud Mental (CIBERSAM), IDIBAPS, and the CERCA Programme / Generalitat de Catalunya (grant numbers PI080247, PI1200906, PI12/00018, 2014SGR1636, and 2014SGR398). The Swedish Research Council, the Stockholm County Council, Karolinska Institutet and the Söderström-Königska Foundation supported this research through grants awarded to Lena Backlund, Louise Frise’n, Catharina Lavebratt and Martin Schalling. The collection of the Geneva sample was supported by the Swiss National Foundation (grants Synapsy 51NF40-158776 and 32003B-125469). The collection of the Romanian sample was supported by U.E.F.I.S.C.D.I., Romania, grant awarded to Maria Grigoroiu-Serbanescu. Open Access funding enabled and organized by CAUL and its Member Institutions.
• dc.format.mimetype application/pdf
• dc.identifier.citation Amare AT, Thalamuthu A, Schubert KO, Fullerton JM, Ahmed M, Hartmann S, et al. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. Mol Psychiatry. 2023 Dec;28(12):5251-61. DOI: 10.1038/s41380-023-02149-1
• dc.identifier.doi http://dx.doi.org/10.1038/s41380-023-02149-1
• dc.identifier.issn 1359-4184
• dc.identifier.uri http://hdl.handle.net/10230/60259
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Mol Psychiatry. 2023 Dec;28(12):5251-61
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/945151
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Bipolar disorder
• dc.subject.keyword Genetics
• dc.subject.keyword Predictive markers
• dc.title Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion