Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study
Authors: Kelsoe John , Ou Anna , Rosenthal Sara , Adli Mazda , Akiyama Kazufumi , Akula Nirmala , Alda Martin , Amare Azmeraw T. , Ardau Raffaella , Arias Bárbara , Aubry Jean-Michel , Backlund Lena , Banzato Claudio , Bauer Michael , Baune Bernhard , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Abesh Bhattacharjee , Biernacka Joanna , Bui Elise , Cervantes Pablo , Chen Guo-Bo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Clark Scott , Colom Francesc , Cousins David , Cruceanu Cristiana , Czerski Piotr , Dantas Clarissa , Dayer Alexandre , Degenhardt Franziska , DePaulo J. Raymond , Etain Bruno , Falkai Peter , Fellendorf Frederike , Ferensztajn-Rochowiak Ewa , Forstner Andreas J. , Frisen Louise , Frye Mark , Fullerton Janice , Gard Sebastien , Garnham Julie , Goes Fernando , Grigoroiu-Serbanescu Maria , Grof Paul , Gruber Oliver , Hashimoto Ryota , Hauser Joanna , Heilbronner Urs , Herms Stefan , Hoffmann Per , Hofmann Andrea , Hou Liping , Jamain Stéphane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kato Tadafumi , Kittel-Schneider Sarah , König Barbara , kuo Po-Hsiu , Kusumi Ichiro , Dalkner Nina , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan , Jaramillo Carlos López , MacQueen Glenda , Maj Mario , Manchia Mirko , Marie-Claire Cynthia , Martinsson Lina , Mattheisen Manuel , McCarthy Michael , McElroy Susan , McMahon Francis , Mitchell Philip , Mitjans Marina , Mondimore Francis , Monteleone Palmiero , Nievergelt Caroline , Nöthen Markus , Novak Tomas , Osby Urban , Ozaki Norio , Papiol Sergi , Perlis Roy , Pfennig Andrea , Potash James , Reich-Erkelenz Daniela , Reif Andreas , Reininghaus Eva , Rietschel Marcella , Rouleau Guy , Rybakowski Janusz K. , Schalling Martin , Schofield Peter , Schubert Klaus Oliver , Schulze Thomas , SCHWEIZER BARBARA , Seemüller Florian , Severino Giovanni , Shekhtman Tatyana , Shilling Paul , Shimoda Kazutaka , Simhandl Christian , slaney claire , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Tighe Sarah , Tortorella Alfonso , Turecki Gustavo , Vieta Eduard , Volkert Julia , Witt Stephanie , Wray Naomi , Wright Adam , Young Trevor , Zandi Peter , Zompo Maria Del 
Published: October 2023

Abstract
Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.