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

Anna H. Ou; Sara B. Rosenthal; Mazda Adli; Kazufumi Akiyama; Nirmala Akula; Martin Alda; Azmeraw T. Amare; Raffaella Ardau; B. rbara 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 R. Dantas; Alexandre Dayer; Maria del Zompo; Franziska Degenhardt; J. Raymond DePaulo; Bruno Étain; Peter Falkai; Frederike Tabea Fellendorf; Ewa Ferensztajn-Rochowiak; Andreas J. Forstner; Louise Frisén; Mark A. Frye; Janice M. Fullerton; S. bastien Gard; Julie S. Garnham; Fernando S. Goes; Maria Grigoroiu-Serbanescu; Paul Grof; Oliver Gruber; Ryota Hashimoto; Joanna Hauser; Urs Heilbronner; Stefan Herms; Per Hoffmann; Andrea Hofmann; Liping Hou; Stephane 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 A. L. pez 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; Tomas 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 K. Rybakowski; Martin Schalling; Peter R. Schofield; K. Oliver Schubert; Thomas G. Schulze; Barbara W. Schweizer; Florian Seemüller; Giovanni Severino; Tatyana Shekhtman; Paul D. Shilling; Kazutaka Shimoda; Christian Simhandl; Claire M. Slaney; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Sarah K. Tighe; Alfonso Tortorella; Gustavo Turecki; Eduard Vieta; Julia Volkert; Stephanie Witt; Naomi R. Wray; Adam Wright; L. Trevor Young; Peter P. Zandi; John R. Kelsoe

doi:10.1038/s41398-024-02811-4

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

Anna H. Ou
, Sara B. Rosenthal
, Mazda Adli
, Kazufumi Akiyama
, Nirmala Akula
, Martin Alda
, Azmeraw T. Amare
, Raffaella Ardau
, B. rbara 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 R. Dantas, Alexandre Dayer, Maria del Zompo, Franziska Degenhardt, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Frederike Tabea Fellendorf, Ewa Ferensztajn-Rochowiak, Andreas J. Forstner, Louise Frisén, Mark A. Frye, Janice M. Fullerton, S. bastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Andrea Hofmann, Liping Hou, Stephane 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 A. L. pez 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, Tomas 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 K. Rybakowski, Martin Schalling, Peter R. Schofield, K. Oliver Schubert, Thomas G. Schulze, Barbara W. Schweizer, Florian Seemüller, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Kazutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Eduard Vieta, Julia Volkert, Stephanie Witt, Naomi R. Wray, Adam Wright, L. Trevor Young, Peter P. Zandi, John R. Kelsoe^*

^*Corresponding author for this work

University of California at San Diego
Charité – Universitätsmedizin Berlin
Center for Psychiatry
Dokkyo Medical University
National Institutes of Health
Dalhousie University
National Institute of Mental Health
University of Adelaide
University of Cagliari
University of Barcelona
ISCIII
University of Geneva
Karolinska University Hospital
Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus, Dresden Germany
University of Münster
Université Paris Cité
Medical University of Graz
Mayo Clinic Rochester, MN
McGill University Health Center
National Taiwan University
University of Bonn
University of Basel
Institute for Ageing and Health, Newcastle University
Douglas Mental Health University Institute
University of Medical Sciences Poznan
Universidade Estadual de Campinas
Johns Hopkins University
University Hospital Munich
Child and Adolescent Psychiatry Research Center
Neuroscience Research Australia
University of New South Wales
Centre Hospitalier Charles Perrens
Alexandru Obregia Hospital
Mood Disorders Center of Ottawa
Georg-August-University
National Center of Neurology and Psychiatry Kodaira
INSERM U955
Université de Lorraine
RIKEN
Goethe University Frankfurt
Landesklinikum Neunkirchen
Hokkaido University
Sahlgrenska Academy
Karolinska Institutet
Assistance publique – Hôpitaux de Paris
Department of Veterans Affairs
Universidad de Antioquia
University of Calgary
University of Campania Luigi Vanvitelli
Aarhus University
University of Cincinnati
University of Salerno
Nagoya University
Ludwig Maximilian University of Munich
Brigham and Women’s Hospital
University of Iowa
Heidelberg University
McGill University
VA Medical Center
Bipolar Center
University of Queensland
University of Toronto

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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.

Original language	English
Article number	109
Journal	Translational psychiatry
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41398-024-02811-4
Publication status	Published - 1 Dec 2024
Externally published	Yes

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Ou, A. H., Rosenthal, S. B., Adli, M., Akiyama, K., Akula, N., Alda, M., Amare, A. T., Ardau, R., Arias, B. R., Aubry, J.-M., Backlund, L., Bauer, M., Baune, B. T., Bellivier, F., Benabarre, A., Bengesser, S., Bhattacharjee, A. K., Biernacka, J. M., Cervantes, P., ... Kelsoe, J. R. (2024). Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study. Translational psychiatry, 14(1), Article 109. https://doi.org/10.1038/s41398-024-02811-4

@article{6ad110ff71f846e3b4e0db20bc065dd7,

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

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.",

author = "Ou, \{Anna H.\} and Rosenthal, \{Sara B.\} and Mazda Adli and Kazufumi Akiyama and Nirmala Akula and Martin Alda and Amare, \{Azmeraw T.\} and Raffaella Ardau and Arias, \{B. rbara\} and Jean-Michel Aubry and Lena Backlund and Michael Bauer and Baune, \{Bernhard T.\} and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Bhattacharjee, \{Abesh Kumar\} and Biernacka, \{Joanna M.\} and Pablo Cervantes and Guo-Bo Chen and Hsi-Chung Chen and Caterina Chillotti and Sven Cichon and Clark, \{Scott R.\} and Francesc Colom and Cousins, \{David A.\} and Cristiana Cruceanu and Czerski, \{Piotr M.\} and Dantas, \{Clarissa R.\} and Alexandre Dayer and \{del Zompo\}, Maria and Franziska Degenhardt and DePaulo, \{J. Raymond\} and Bruno {\'E}tain and Peter Falkai and Fellendorf, \{Frederike Tabea\} and Ewa Ferensztajn-Rochowiak and Forstner, \{Andreas J.\} and Louise Fris{\'e}n and Frye, \{Mark A.\} and Fullerton, \{Janice M.\} and Gard, \{S. bastien\} and Garnham, \{Julie S.\} and Goes, \{Fernando S.\} and Maria Grigoroiu-Serbanescu and Paul Grof and Oliver Gruber and Ryota Hashimoto and Joanna Hauser and Urs Heilbronner and Stefan Herms and Per Hoffmann and Andrea Hofmann and Liping Hou and Stephane Jamain and Esther Jim{\'e}nez and Jean-Pierre Kahn and Layla Kassem and Tadafumi Kato and Sarah Kittel-Schneider and Barbara K{\"o}nig and Po-Hsiu Kuo and Ichiro Kusumi and Nina Lackner and Gonzalo Laje and Mikael Land{\'e}n and Catharina Lavebratt and Marion Leboyer and Leckband, \{Susan G.\} and Jaramillo, \{Carlos A. L. pez\} and Glenda MacQueen and Mario Maj and Mirko Manchia and Cynthia Marie-Claire and Lina Martinsson and Manuel Mattheisen and McCarthy, \{Michael J.\} and McElroy, \{Susan L.\} and McMahon, \{Francis J.\} and Mitchell, \{Philip B.\} and Marina Mitjans and Mondimore, \{Francis M.\} and Palmiero Monteleone and Nievergelt, \{Caroline M.\} and N{\"o}then, \{Markus M.\} and Tomas Nov{\'a}k and Urban {\"O}sby and Norio Ozaki and Sergi Papiol and Perlis, \{Roy H.\} and Claudia Pisanu and Potash, \{James B.\} and Andrea Pfennig and Daniela Reich-Erkelenz and Andreas Reif and Reininghaus, \{Eva Z.\} and Marcella Rietschel and Rouleau, \{Guy A.\} and Rybakowski, \{Janusz K.\} and Martin Schalling and Schofield, \{Peter R.\} and Schubert, \{K. Oliver\} and Schulze, \{Thomas G.\} and Schweizer, \{Barbara W.\} and Florian Seem{\"u}ller and Giovanni Severino and Tatyana Shekhtman and Shilling, \{Paul D.\} and Kazutaka Shimoda and Christian Simhandl and Slaney, \{Claire M.\} and Alessio Squassina and Thomas Stamm and Pavla Stopkova and Tighe, \{Sarah K.\} and Alfonso Tortorella and Gustavo Turecki and Eduard Vieta and Julia Volkert and Stephanie Witt and Wray, \{Naomi R.\} and Adam Wright and Young, \{L. Trevor\} and Zandi, \{Peter P.\} and Kelsoe, \{John R.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

day = "1",

doi = "10.1038/s41398-024-02811-4",

language = "English",

volume = "14",

journal = "Translational psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Ou, AH, Rosenthal, SB, Adli, M, Akiyama, K, Akula, N, Alda, M, Amare, AT, Ardau, R, Arias, BR, Aubry, J-M, Backlund, L, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Cervantes, P, Chen, G-B, Chen, H-C, 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, SB, 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, J-P, Kassem, L, Kato, T, Kittel-Schneider, S, König, B, Kuo, P-H, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CALP, 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, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Vieta, E, Volkert, J, Witt, S, Wray, NR, Wright, A, Young, LT, Zandi, PP & Kelsoe, JR 2024, 'Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study', Translational psychiatry, vol. 14, no. 1, 109. https://doi.org/10.1038/s41398-024-02811-4

TY - JOUR

T1 - Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks

T2 - a multi-omics replication study

AU - Ou, Anna H.

AU - Rosenthal, Sara B.

AU - Adli, Mazda

AU - Akiyama, Kazufumi

AU - Akula, Nirmala

AU - Alda, Martin

AU - Amare, Azmeraw T.

AU - Ardau, Raffaella

AU - Arias, B. rbara

AU - Aubry, Jean-Michel

AU - Backlund, Lena

AU - Bauer, Michael

AU - Baune, Bernhard T.

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Bhattacharjee, Abesh Kumar

AU - Biernacka, Joanna M.

AU - Cervantes, Pablo

AU - Chen, Guo-Bo

AU - Chen, Hsi-Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Clark, Scott R.

AU - Colom, Francesc

AU - Cousins, David A.

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dantas, Clarissa R.

AU - Dayer, Alexandre

AU - del Zompo, Maria

AU - Degenhardt, Franziska

AU - DePaulo, J. Raymond

AU - Étain, Bruno

AU - Falkai, Peter

AU - Fellendorf, Frederike Tabea

AU - Ferensztajn-Rochowiak, Ewa

AU - Forstner, Andreas J.

AU - Frisén, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gard, S. bastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grigoroiu-Serbanescu, Maria

AU - Grof, Paul

AU - Gruber, Oliver

AU - Hashimoto, Ryota

AU - Hauser, Joanna

AU - Heilbronner, Urs

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Hofmann, Andrea

AU - Hou, Liping

AU - Jamain, Stephane

AU - Jiménez, Esther

AU - Kahn, Jean-Pierre

AU - Kassem, Layla

AU - Kato, Tadafumi

AU - Kittel-Schneider, Sarah

AU - König, Barbara

AU - Kuo, Po-Hsiu

AU - Kusumi, Ichiro

AU - Lackner, Nina

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lavebratt, Catharina

AU - Leboyer, Marion

AU - Leckband, Susan G.

AU - Jaramillo, Carlos A. L. pez

AU - MacQueen, Glenda

AU - Maj, Mario

AU - Manchia, Mirko

AU - Marie-Claire, Cynthia

AU - Martinsson, Lina

AU - Mattheisen, Manuel

AU - McCarthy, Michael J.

AU - McElroy, Susan L.

AU - McMahon, Francis J.

AU - Mitchell, Philip B.

AU - Mitjans, Marina

AU - Mondimore, Francis M.

AU - Monteleone, Palmiero

AU - Nievergelt, Caroline M.

AU - Nöthen, Markus M.

AU - Novák, Tomas

AU - Ösby, Urban

AU - Ozaki, Norio

AU - Papiol, Sergi

AU - Perlis, Roy H.

AU - Pisanu, Claudia

AU - Potash, James B.

AU - Pfennig, Andrea

AU - Reich-Erkelenz, Daniela

AU - Reif, Andreas

AU - Reininghaus, Eva Z.

AU - Rietschel, Marcella

AU - Rouleau, Guy A.

AU - Rybakowski, Janusz K.

AU - Schalling, Martin

AU - Schofield, Peter R.

AU - Schubert, K. Oliver

AU - Schulze, Thomas G.

AU - Schweizer, Barbara W.

AU - Seemüller, Florian

AU - Severino, Giovanni

AU - Shekhtman, Tatyana

AU - Shilling, Paul D.

AU - Shimoda, Kazutaka

AU - Simhandl, Christian

AU - Slaney, Claire M.

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stopkova, Pavla

AU - Tighe, Sarah K.

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Vieta, Eduard

AU - Volkert, Julia

AU - Witt, Stephanie

AU - Wray, Naomi R.

AU - Wright, Adam

AU - Young, L. Trevor

AU - Zandi, Peter P.

AU - Kelsoe, John R.

PY - 2024/12/1

Y1 - 2024/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85185915765

U2 - 10.1038/s41398-024-02811-4

DO - 10.1038/s41398-024-02811-4

M3 - Article

C2 - 38395906

SN - 2158-3188

VL - 14

JO - Translational psychiatry

JF - Translational psychiatry

IS - 1

M1 - 109

ER -

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

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