Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study
Anna Ou, Sara Brin Rosenthal, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Martin Alda, Azmeraw T. Amare, Raffaella Ardau, Bárbara Arias, Jean‐Michel Aubry, Lena Backlund, Michael Bauer, Bernhard T. Baune, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Pablo Cervantes, Guo‐Bo Chen, Hsi‐Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Clarissa de Rosalmeida Dantas, Alexandre Dayer, Maria Del Zompo, Franziska Degenhardt, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Frederike T. Fellendorf, Ewa Ferensztajn‐Rochowiak, Andreas J. Forstner, Louise Frisén, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie Garnham, Fernando S. Goes, Maria Grigoroiu‐Serbânescu, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Andrea Hofmann, Liping Hou, Stéphane Jamain, Esther Jiménez, Jean‐Pierre Kahn, Layla Kassem, Tadafumi Kato, Sarah Kittel‐Schneider, Barbara König, Po‐Hsiu Kuo, Ichiro Kusumi, Nina Lackner, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos López‐Jaramillo, Glenda MacQueen, Mario Maj, Mirko Manchia, Cynthia Marie‐Claire, Lina Martinsson, Manuel Mattheisen, Michael J. McCarthy, Susan L. McElroy, Francis J. McMahon, Philip B. Mitchell, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomáš Novák, Urban Ösby, Norio Ozaki, Sergi Papiol, Roy H. Perlis, Claudia Pisanu, James B. Potash, Andrea Pfennig, Daniela Reich‐Erkelenz, Andreas Reif, Eva Z. Reininghaus, Marcella Rietschel, Guy A. Rouleau, Janusz Rybakowski, Martin Schalling
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 2039 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.