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. 2024 Apr 3;14(1):174.
doi: 10.1038/s41398-024-02865-4.

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

Marisol Herrera-Rivero  1   2   3 , Karina Gutiérrez-Fragoso  4 ; International Consortium on Lithium Genetics (ConLi+Gen); Joachim Kurtz  3   5 , Bernhard T Baune  6   7   8   9
Collaborators, Affiliations

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

Marisol Herrera-Rivero et al. Transl Psychiatry. .

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.

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Conflict of interest statement

Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbvie, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GH Research, Glaxo-Smith-Kline, Janssen, Lundbeck, Orion, Otsuka, Pfizer, Roche, Rovi, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley Medical Research Institute and Viatris. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Takeda. Bernhard T. Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén has received lecture honoraria from Lundbeck. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. Scott R. Clark has received grants and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia. The rest of authors have no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. Exploratory findings for the ImmuneSet in ConLi+Gen.
A Gene-based phenogram of associations of the ImmuneSet with Li response and clinical features in ConLi+Gen. B Protein-protein interaction network of Li response phenotype associations in the ImmuneSet. Circles represent input genes and diamonds represent linker genes. Dotted lines denote predicted interactions.
Fig. 2
Fig. 2. Results of eQTL annotation and PGS association testing.
A Gene-based phenogram of eQTL annotations for the exploratory-level findings of the ImmuneSet in ConLi+Gen. Those eQTL genes that were different from the mapped gene and those that were the same are presented in circle and diamond shapes, respectively. Only protein-coding genes are shown. In addition, overlaps with BP genetic associations reported in the GWAS Catalog are presented. B Exploratory findings from the association analyses of immune-related polygenic scores and BP phenotypes in ConLi+Gen “GWAS1”. The heatmap shows the estimates (scaled by column) obtained for each PGS-phenotype pair. Increasing color darkness alludes to increasing effect, with red and blue colors representing positive and negative values, respectively. *p < 0.05, **p < 0.01.
See this image and copyright information in PMC

Update of

  • Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.
    Herrera-Rivero M, Gutiérrez-Fragoso K, Thalamuthu A, Amare AT, Adli M, Akiyama K, Akula N, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Abesh B, Biernacka J, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark S, Colom F, Cruceanu C, Czerski P, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisen L, Frye M, Fullerton J, Gallo C, Gard S, Garnham J, Goes F, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu Y, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kurtz J, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband S, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy M, McElroy SL, Millischer V, Mitjans M, Mondimore F, Monteleone P, Nievergelt C, Novak T, Nöthen M, Odonovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash J, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau G, Rybakowski JK, Schalling M, Schofield P, Schubert KO, Schulte E, Schweizer B, Severino G, Shekhtman T, Shilling P, Shimoda K, Simhandl C, Slaney C, Sq… See abstract for full author list ➔ Herrera-Rivero M, et al. Res Sq [Preprint]. 2023 Jun 26:rs.3.rs-3068352. doi: 10.21203/rs.3.rs-3068352/v1. Res Sq. 2023. Update in: Transl Psychiatry. 2024 Apr 3;14(1):174. doi: 10.1038/s41398-024-02865-4. PMID: 37461719 Free PMC article. Updated. Preprint.

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