Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder
Authors: Herrera-Rivero Marisol , Gutiérrez-Fragoso Karina , 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 , Abesh Bhattacharjee , Biernacka Joanna , Birner Armin , Cearns Micah , Cervantes Pablo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Clark Scott , Colom Francesc , Cruceanu Cristiana , Czerski Piotr , Dalkner Nina , Degenhardt Franziska , Zompo Maria Del , DePaulo J. Raymond , Etain Bruno , Falkai Peter , Ferensztajn-Rochowiak Ewa , Forstner Andreas J. , Frank Josef , Frisen Louise , Frye Mark , Fullerton Janice , Gallo Carla , Gard Sebastien , Garnham Julie , Goes Fernando , Grigoroiu-Serbanescu Maria , Grof Paul , Hashimoto Ryota , Hasler Roland , Hauser Joanna , Heilbronner Urs , Herms Stefan , Hoffmann Per , Hou Liping , Hsu YiHsiang , Jamain Stéphane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kato Tadafumi , Kelsoe John , Kittel-Schneider Sarah , kuo Po-Hsiu , Kurtz Joachim , Kusumi Ichiro , König Barbara , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan , Maj Mario , Manchia Mirko , Marie-Claire Cynthia , Martinsson Lina , McCarthy Michael , McElroy Susan L. , Millischer Vincent , Mitjans Marina , Mondimore Francis , Monteleone Palmiero , Nievergelt Caroline , Novak Tomas , Nöthen Markus , odonovan claire , Ozaki Norio , Papiol Sergi , Pfennig Andrea , Pisanu Claudia , Potash James , Reif Andreas , Reininghaus Eva , Richard-Lepouriel Hélène , Roberts Gloria , Rouleau Guy , Rybakowski Janusz K. , Schalling Martin , Schofield Peter , Schubert Klaus Oliver , Schulte Eva , SCHWEIZER BARBARA , Severino Giovanni , Shekhtman Tatyana , Shilling Paul , Shimoda Kazutaka , Simhandl Christian , slaney claire , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Streit Fabian , Ayele Fasil , Tortorella Alfonso , Turecki Gustavo , Veeh Julia , Vieta Eduard , Viswanath Biju , Witt Stephanie , Zandi Peter , Alda Martin , Bauer Michael , McMahon Francis , Mitchell Philip , Rietschel Marcella , Schulze Thomas , Baune Bernhard 
Published: June 2023

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 investigated 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 (4,925) 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 = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10− 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.