Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study

A. H., Ou; Rosenthal, S. B.; Adli, M.; Akiyama, K.; Akula, N.; Alda, M.; Amare, A. T.; Ardau, R.; Arias, B.; Aubry, J. -M.; Backlund, L.; Bauer, M.; Baune, B. T.; Bellivier, F.; Benabarre, A.; Bengesser, S.; Bhattacharjee, A. K.; Biernacka, J. M.; Cervantes, P.; Chen, G. -B.; Chen, H. -C.; Chillotti, C.; Cichon, S.; Clark, S. R.; Colom, F.; Cousins, D. A.; Cruceanu, C.; Czerski, P. M.; Dantas, C. R.; Dayer, A.; Del Zompo, M.; Degenhardt, F.; Depaulo, J. R.; Etain, B.; Falkai, P.; Fellendorf, F. T.; Ferensztajn-Rochowiak, E.; Forstner, A. J.; Frisen, L.; Frye, M. A.; Fullerton, J. M.; Gard, S.; Garnham, J. S.; Goes, F. S.; Grigoroiu-Serbanescu, M.; Grof, P.; Gruber, O.; Hashimoto, R.; Hauser, J.; Heilbronner, U.; Herms, S.; Hoffmann, P.; Hofmann, A.; Hou, L.; Jamain, S.; Jimenez, E.; Kahn, J. -P.; Kassem, L.; Kato, T.; Kittel-Schneider, S.; Konig, B.; Kuo, P. -H.; Kusumi, I.; Lackner, N.; Laje, G.; Landen, M.; Lavebratt, C.; Leboyer, M.; Leckband, S. G.; Jaramillo, C. A. L.; Macqueen, G.; Maj, M.; Manchia, M.; Marie-Claire, C.; Martinsson, L.; Mattheisen, M.; Mccarthy, M. J.; Mcelroy, S. L.; Mcmahon, F. J.; Mitchell, P. B.; Mitjans, M.; Mondimore, F. M.; Monteleone, P.; Nievergelt, C. M.; Nothen, M. M.; Novak, T.; Osby, U.; Ozaki, N.; Papiol, S.; Perlis, R. H.; Pisanu, C.; Potash, J. B.; Pfennig, A.; Reich-Erkelenz, D.; Reif, A.; Reininghaus, E. Z.; Rietschel, M.; Rouleau, G. A.; Rybakowski, J. K.; Schalling, M.; Schofield, P. R.; Schubert, K. O.; Schulze, T. G.; Schweizer, B. W.; Seemuller, F.; Severino, G.; Shekhtman, T.; Shilling, P. D.; Shimoda, K.; Simhandl, C.; Slaney, C. M.; Squassina, A.; Stamm, T.; Stopkova, P.; Tighe, S. K.; Tortorella, A.; Turecki, G.; Vieta, E.; Volkert, J.; Witt, S.; Wray, N. R.; Wright, A.; Young, L. T.; Zandi, P. P.; Kelsoe, J. R.

doi:10.1038/s41398-024-02811-4

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.