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[Preprint]. 2023 Oct 3:rs.3.rs-3258813.

doi: 10.21203/rs.3.rs-3258813/v1.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study

John Kelsoe¹, Anna Ou¹, Sara Rosenthal, Mazda Adli, Kazufumi Akiyama², Nirmala Akula³, Martin Alda⁴, Azmeraw T Amare⁵, Raffaella Ardau⁶, Bárbara Arias⁷, Jean-Michel Aubry⁸, Lena Backlund, Claudio Banzato, Michael Bauer⁹, Bernhard Baune¹⁰, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Bhattacharjee Abesh, Joanna Biernacka¹¹, Elise Bui, Pablo Cervantes¹², Guo-Bo Chen, Hsi-Chung Chen¹³, Caterina Chillotti, Sven Cichon¹¹, Scott Clark¹⁴, Francesc Colom, David Cousins, Cristiana Cruceanu¹⁵, Piotr Czerski¹⁶, Clarissa Dantas, Alexandre Dayer¹⁷, Franziska Degenhardt¹⁸, J Raymond DePaulo¹⁹, Bruno Etain, Peter Falkai²⁰, Frederike Fellendorf, Ewa Ferensztajn-Rochowiak, Andreas J Forstner²¹, Louise Frisen²², Mark Frye¹¹, Janice Fullerton²³, Sebastien Gard, Julie Garnham, Fernando Goes, Maria Grigoroiu-Serbanescu²⁴, Paul Grof, Oliver Gruber, Ryota Hashimoto²⁵, Joanna Hauser, Urs Heilbronner²⁶, Stefan Herms, Per Hoffmann²⁷, Andrea Hofmann, Liping Hou²⁸, Stéphane Jamain²⁹, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem²², Tadafumi Kato³⁰, Sarah Kittel-Schneider, Barbara König, Po-Hsiu Kuo³¹, Ichiro Kusumi³², Nina Dalkner, Gonzalo Laje, Mikael Landén³³, Catharina Lavebratt³⁴, Marion Leboyer, Susan Leckband, Carlos López Jaramillo, Glenda MacQueen, Mario Maj³⁵, Mirko Manchia⁴, Cynthia Marie-Claire³⁶, Lina Martinsson³⁴, Manuel Mattheisen¹⁹, Michael McCarthy, Susan McElroy³⁷, Francis McMahon³⁸, Philip Mitchell³⁹, Marina Mitjans⁴⁰, Francis Mondimore²³, Palmiero Monteleone⁴¹, Caroline Nievergelt⁴², Markus Nöthen²², Tomas Novak⁴³, Urban Osby³⁴, Norio Ozaki⁴⁴, Sergi Papiol²⁰, Roy Perlis⁴⁵, Andrea Pfennig⁴⁶, James Potash, Daniela Reich-Erkelenz, Andreas Reif⁴⁷, Eva Reininghaus, Marcella Rietschel⁴⁸, Guy Rouleau⁴⁹, Janusz K Rybakowski¹⁶, Martin Schalling³⁴, Peter Schofield²³, Klaus Oliver Schubert¹⁴, Thomas Schulze⁵⁰, Barbara Schweizer, Florian Seemüller, Giovanni Severino⁵¹, Tatyana Shekhtman, Paul Shilling, Kazutaka Shimoda, Christian Simhandl, Claire Slaney, Alessio Squassina⁵², Thomas Stamm⁵³, Pavla Stopkova, Sarah Tighe, Alfonso Tortorella⁵⁴, Gustavo Turecki⁵⁵, Eduard Vieta⁵⁶, Julia Volkert, Stephanie Witt⁵⁷, Naomi Wray⁵⁸, Adam Wright, Trevor Young, Peter Zandi¹⁹, Maria Del Zompo⁵¹

Affiliations

¹ University of California San Diego.
² Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University.
³ National Institutes of Health, US Dept of Health & Human Services.
⁴ Dalhousie University.
⁵ University of Adelaide, AUSTRALIA.
⁶ Hospital University Agency of Cagliari.
⁷ Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM.
⁸ Geneva University Hospitals.
⁹ University Hospital Carl Gustav Carus.
¹⁰ University of Münster.
¹¹ Mayo Clinic.
¹² McGill University Health Centre.
¹³ 3Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan 4Department of Psychiatry, Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
¹⁴ University of Adelaide.
¹⁵ Max Plank Institute for Psychiatry.
¹⁶ Poznan University of Medical Sciences.
¹⁷ University of Geneva.
¹⁸ University of Essen.
¹⁹ Johns Hopkins University.
²⁰ University Hospital LMU.
²¹ University of Bonn, School of Medicine & University Hospital Bonn.
²² School of Medicine & University Hospital Bonn.
²³ Neuroscience Research Australia.
²⁴ Alexandru Obregia Clinical Psychiatric Hospital.
²⁵ National Center of Neurology and Psychiatry.
²⁶ Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich.
²⁷ Institute of Human Genetics.
²⁸ National Institute of Mental Health Intramural Research Program, National Institutes of Health.
²⁹ Univ Paris Est Creteil, INSERM, IMRB.
³⁰ Juntendo University Graduate School of Medicine.
³¹ College of Public Health, National Taiwan University, Taipei, Taiwan.
³² Hokkaido University Graduate School of Medicine.
³³ Gothenburg University.
³⁴ Karolinska Institutet.
³⁵ University of Naples, Italy.
³⁶ INSERM UMR-S 1144.
³⁷ Lindner Center.
³⁸ National Institute of Mental Health Intramural Research Program; National Institutes of Health.
³⁹ University of New South Wales.
⁴⁰ Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁴¹ University of Salerno, University of Naples SUN.
⁴² University of California, San Diego.
⁴³ National Institute of Mental Health, Klecany.
⁴⁴ Nagoya University.
⁴⁵ Massachusetts General Hospital.
⁴⁶ University Hospital Carl Gustav Carus, TU Dresden.
⁴⁷ University Hospital Frankfurt, Germany.
⁴⁸ University of Mannheim.
⁴⁹ McGill University.
⁵⁰ University of Munich.
⁵¹ University of Cagliari.
⁵² Universita degli Studi Di Cagliari.
⁵³ Charité - Universitätsmedizin Berlin, Campus Charité Mitte.
⁵⁴ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁵⁵ Douglas Institute, Department of Psychiatry, McGill University.
⁵⁶ Hospital Clinic of Barcelona.
⁵⁷ University Medical Centre Mannheim.
⁵⁸ University of Queensland.

PMID: 37886563
PMCID: PMC10602152
DOI: 10.21203/rs.3.rs-3258813/v1

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study

John Kelsoe et al. Res Sq. 2023.

[Preprint]. 2023 Oct 3:rs.3.rs-3258813.

doi: 10.21203/rs.3.rs-3258813/v1.

Authors

Affiliations

¹ University of California San Diego.
² Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University.
³ National Institutes of Health, US Dept of Health & Human Services.
⁴ Dalhousie University.
⁵ University of Adelaide, AUSTRALIA.
⁶ Hospital University Agency of Cagliari.
⁷ Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM.
⁸ Geneva University Hospitals.
⁹ University Hospital Carl Gustav Carus.
¹⁰ University of Münster.
¹¹ Mayo Clinic.
¹² McGill University Health Centre.
¹³ 3Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan 4Department of Psychiatry, Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
¹⁴ University of Adelaide.
¹⁵ Max Plank Institute for Psychiatry.
¹⁶ Poznan University of Medical Sciences.
¹⁷ University of Geneva.
¹⁸ University of Essen.
¹⁹ Johns Hopkins University.
²⁰ University Hospital LMU.
²¹ University of Bonn, School of Medicine & University Hospital Bonn.
²² School of Medicine & University Hospital Bonn.
²³ Neuroscience Research Australia.
²⁴ Alexandru Obregia Clinical Psychiatric Hospital.
²⁵ National Center of Neurology and Psychiatry.
²⁶ Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich.
²⁷ Institute of Human Genetics.
²⁸ National Institute of Mental Health Intramural Research Program, National Institutes of Health.
²⁹ Univ Paris Est Creteil, INSERM, IMRB.
³⁰ Juntendo University Graduate School of Medicine.
³¹ College of Public Health, National Taiwan University, Taipei, Taiwan.
³² Hokkaido University Graduate School of Medicine.
³³ Gothenburg University.
³⁴ Karolinska Institutet.
³⁵ University of Naples, Italy.
³⁶ INSERM UMR-S 1144.
³⁷ Lindner Center.
³⁸ National Institute of Mental Health Intramural Research Program; National Institutes of Health.
³⁹ University of New South Wales.
⁴⁰ Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁴¹ University of Salerno, University of Naples SUN.
⁴² University of California, San Diego.
⁴³ National Institute of Mental Health, Klecany.
⁴⁴ Nagoya University.
⁴⁵ Massachusetts General Hospital.
⁴⁶ University Hospital Carl Gustav Carus, TU Dresden.
⁴⁷ University Hospital Frankfurt, Germany.
⁴⁸ University of Mannheim.
⁴⁹ McGill University.
⁵⁰ University of Munich.
⁵¹ University of Cagliari.
⁵² Universita degli Studi Di Cagliari.
⁵³ Charité - Universitätsmedizin Berlin, Campus Charité Mitte.
⁵⁴ Department of Psychiatry, University of Perugia, Perugia, Italy.
⁵⁵ Douglas Institute, Department of Psychiatry, McGill University.
⁵⁶ Hospital Clinic of Barcelona.
⁵⁷ University Medical Centre Mannheim.
⁵⁸ University of Queensland.

PMID: 37886563
PMCID: PMC10602152
DOI: 10.21203/rs.3.rs-3258813/v1

Update in

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.
Ou AH, Rosenthal SB, Adli M, Akiyama K, Akula N, Alda M, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bauer M, Baune BT, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dantas CR, Dayer A, Del Zompo M, Degenhardt F, DePaulo JR, Étain B, Falkai P, Fellendorf FT, Ferensztajn-Rochowiak E, Forstner AJ, Frisén L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Gruber O, Hashimoto R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hofmann A, Hou L, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kittel-Schneider S, König B, Kuo PH, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Maj M, Manchia M, Marie-Claire C, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, McMahon FJ, Mitchell PB, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, Ösby U, Ozaki N, Papiol S, Perlis RH, Pisanu C, Potash JB, Pfennig A, Reich-Erkelenz D, Reif A, Reininghaus EZ, Rietschel M, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulze TG, Sch… See abstract for full author list ➔ Ou AH, et al. Transl Psychiatry. 2024 Feb 23;14(1):109. doi: 10.1038/s41398-024-02811-4. Transl Psychiatry. 2024. PMID: 38395906 Free PMC article.

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.

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Conflict of interest statement

MAd has received a grant from Servier, speaker’s fees from Servier, Lundbeck, Aristo, Parexel, Gilead, ViiV, Deutsche Bank, MSD, and MyTomorrows, plus a non-financial support from Lundbeck. KA has received speaker’s fees from Taisho Toyama Pharmaceutical. MAl is funded by a grant of the Canadian Institutes of Health Research. MB has received speaker’s fees from AstraZeneca, Pfizer, Lilly, Lundbeck, GlaxoSmithKline, Servier, and Ferrer Internacional. BÉ received non-financial support from Labex Biopsy and Fondation Fondamental. RH received grants and speaker honoraria from Dainippon Sumitomo Pharma and Novartis plus speaker honoraria from Eli Lilly Japan, GlaxoSmithKline, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical, Astellas Pharma, Pfizer, and the Yoshitomiyakuhin Corporation. TK received a grant from Takeda Pharmaceutical and fees from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka Pharmaceutical, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, PfizerJapan, Mochida Pharmaceutical, Shionogi & Co, Janssen Pharmaceutical, Yoshitomiyakuhin Corporation, Agilent Technologies, Astellas Pharma, and Wako Pure Chemical Industries. IK received grants and fees from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis, Otsuka, Ono Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Shionogi, and Yoshitomi Pharmaceutical; he received grants from AbbVie GK, Asahi Kasei Pharma, Boehringer Ingelheim, Chugai Pharmaceutical, and Daiichi Sankyo and fees from Astellas Pharma and Janssen Pharmaceutical. MJM served as unpaid consultant for Pathway Genomic (San Diego, USA). SLM received a grant and fees from Naurex and Shire, further grants from Alkermes, Cephalon, Forest, Marriott Foundation, Orexigen Therapeutics, and Takeda Pharmaceutical, he further has served on the advisory boards for Bracket, Hoffmann-La Roche, MedAvante, Sunovion and received fees from Novo Nordisk. RHP received personal fees from RID Ventures, Genomind LLC, Healthrageous, P zer, Perfect Health, Proteus, and Psybrain. PRS received a grant from NHMRC. TGS received a grant and fees from Roche Pharmaceuticals. TSt received personal fees from Servier, Lundbeck, and Bristol-Myers Squibb. MM has received grants from Lundbeck and Angelini. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. SRC has participated in advisory and educational boards and received speaker’s fees from Janssen-Cilag, Lundbeck, Otsuka, and Servier; research funding from Janssen-Cilag, Lundbeck, Otsuka, and Gilead; and data sharing from Viatris Australia. ML has received lecture honoraria from Lundbeck pharmaceuticals. All above listed interests are outside of the submitted work. All other authors declare no competing interests.

Figures

**Figure 1. Overlap Between KEGG Focal adhesion and Top 500 Genes**
KEGG hsa04510 pathway for focal adhesion adapted to illustrate gene overlap. Genes in yellow overlap with the 500 gene NAGA network.

**Figure 2. Overlap Between KEGG ECM-receptor interaction and Top 500 Genes**
KEGG hsa04512 pathway for ECM-receptor interaction adapted to illustrate gene overlap. Genes in yellow overlap with the 500 gene NAGA network.

**Figure 3. Overlap Between KEGG PI3k-Akt and Top 500 Genes**
KEGG hsa04151 pathway for PI3k-Akt signaling adapted to illustrate gene overlap. Genes in yellow overlap with the 500 gene NAGA network.

See this image and copyright information in PMC

References

1. Dome P., Rihmer Z. & Gonda X. Suicide Risk in Bipolar Disorder: A Brief Review. Medicina 55, (2019). - PMC - PubMed
1. Cipriani A., Hawton K., Stockton S. & Geddes J. R. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 346, f3646 (2013). - PubMed
1. Plans L. et al. Association between completed suicide and bipolar disorder: A systematic review of the literature. J. Affect. Disord. 242, 111–122 (2019). - PubMed
1. Sajatovic M. Bipolar disorder: disease burden. Am. J. Manag. Care 11, S80–4 (2005). - PubMed
1. Rybakowski J. K. Lithium. Eur. Neuropsychopharmacol. 57, 86–87 (2022). - PubMed

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This is a preprint.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study

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Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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