Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder
Authors: Herrera-Rivero Marisol , Gutiérrez-Fragoso Karina ,   International Consortium on Lithium Genetics (ConLi+Gen), Thalamuthu Anbupalam , Amare Azmeraw T. , Adli Mazda , Akiyama Kazufumi , Akula Nirmala , Ardau Raffaella , Arias Bárbara , Aubry Jean-Michel , Backlund Lena , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Bhattacharjee Abesh Kumar , Biernacka Joanna M. , Birner Armin , Cearns Micah , Cervantes Pablo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Clark Scott R. , Colom Francesc , Cruceanu Cristiana , Czerski Piotr M. , Dalkner Nina , Degenhardt Franziska , Del Zompo Maria , DePaulo J. Raymond , Etain Bruno , Falkai Peter , Ferensztajn-Rochowiak Ewa , Forstner Andreas J. , Frank Josef , Frisén Louise , Frye Mark A. , Fullerton Janice M. , Gallo Carla , Gard Sébastien , Garnham Julie S. , Goes Fernando S. , Grigoroiu-Serbanescu Maria , Grof Paul , Hashimoto Ryota , Hasler Roland , Hauser Joanna , Heilbronner Urs , Herms Stefan , Hoffmann Per , Hou Liping , Hsu Yi-Hsiang , Jamain Stéphane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kato Tadafumi , Kelsoe John , Kittel-Schneider Sarah , Kuo Po-Hsiu , Kusumi Ichiro , König Barbara , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan G. , Maj Mario , Manchia Mirko , Marie-Claire Cynthia , Martinsson Lina , McCarthy Michael J. , McElroy Susan L. , Millischer Vincent , Mitjans Marina , Mondimore Francis M. , Monteleone Palmiero , Nievergelt Caroline M. , Novák Tomas , Nöthen Markus M. , O’Donovan Claire , Ozaki Norio , Papiol Sergi , Pfennig Andrea , Pisanu Claudia , Potash James B. , Reif Andreas , Reininghaus Eva , Richard-Lepouriel Hélène , Roberts Gloria , Rouleau Guy A. , Rybakowski Janusz K. , Schalling Martin , Schofield Peter R. , Schubert Klaus Oliver , Schulte Eva C. , Schweizer Barbara W. , Severino Giovanni , Shekhtman Tatyana , Shilling Paul D. , Shimoda Katzutaka , Simhandl Christian , Slaney Claire M. , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Streit Fabian , Tekola-Ayele Fasil , Tortorella Alfonso , Turecki Gustavo , Veeh Julia , Vieta Eduard , Viswanath Biju , Witt Stephanie H. , Zandi Peter P. , Alda Martin , Bauer Michael , McMahon Francis J. , Mitchell Philip B. , Rietschel Marcella , Schulze Thomas G. , Kurtz Joachim , Baune Bernhard T. 
Published: April 2024

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.