Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

Herrera-Rivero M, Gutiérrez-Fragoso K, Kurtz J, Baune BT, Thalamuthu A, Amare AT, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O’Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Streit F, Tekola-Ayele F, Tortorella A, Turecki G, Veeh J, Vieta E, Viswanath B, Witt SH, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Rietschel M, Schulze TG (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 14

Article Number: 174

Journal Issue: 1

DOI: 10.1038/s41398-024-02865-4

Abstract

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi⁺Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10⁻⁴) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.

Involved external institutions

Johns Hopkins University (JHU) United States (USA) (US) Universitätsklinikum Bonn Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Dokkyo Medical University Japan (JP) National Institute of Mental Health Information Resource Center United States (USA) (US) Hospital University Agency of Cagliari Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Geneva University Hospitals / Hôpitaux universitaires de Genève (HUG) Switzerland (CH) Karolinska Institute Sweden (SE) Université Sorbonne Paris Cité France (FR) Medizinische Universität Graz Austria (AT) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Mayo Clinic United States (USA) (US) University of Adelaide Australia (AU) Università degli Studi di Cagliari Italy (IT) Dalhousie University Canada (CA) Université de Lorraine France (FR) Hospital del Mar Spain (ES) Juntendo University Japan (JP) Douglas Mental Health University Institute Canada (CA) Universitätsklinikum Würzburg Germany (DE) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) National Taiwan University (NTU) Taiwan (TW) Städtisches Klinikum Neunkirchen Germany (DE) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Harvard University United States (USA) (US) Forschungszentrum Jülich / Research Centre Jülich (FZJ) Germany (DE) VA San Diego Healthcare System United States (USA) (US) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) University of Cincinnati United States (USA) (US) Neuroscience Research Australia NeuRA Australia (AU) Centre Hospitalier Charles Perrens (CHCP) France (FR) Università degli Studi di Salerno Italy (IT) National Institute of Mental Health (NIMH) / Národní ústav duševního zdraví (NUDZ) Czech Republic (CZ) Mood Disorders Ottawa Canada (CA) Nagoya University / 名古屋大学 Japan (JP) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) University of New South Wales (UNSW) Australia (AU) Universitätsspital Basel Switzerland (CH) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) Harvard T.H. Chan School of Public Health United States (USA) (US) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Universidad Peruana Cayetano Heredia Peru (PE) Sigmund-Freud-Privatuniversität Wien (SFU) / Sigmund Freud University Austria (AT) US National Institutes of Health (NIH) United States (USA) (US) Università degli Studi di Perugia Italy (IT) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) National Institute of Mental Health and Neuroscience (NIMHANS) India (IN)

How to cite

APA:

Herrera-Rivero, M., Gutiérrez-Fragoso, K., Kurtz, J., Baune, B.T., Thalamuthu, A., Amare, A.T.,... Schulze, T.G. (2024). Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder. Translational Psychiatry, 14(1). https://doi.org/10.1038/s41398-024-02865-4

MLA:

Herrera-Rivero, Marisol, et al. "Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder." Translational Psychiatry 14.1 (2024).

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