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

Ou A. H.;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.

2024-01-01

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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.