. 2024 Feb 23;14(1):109.

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 Ou¹, Sara B Rosenthal², Mazda Adli^{3

4}, Kazufumi Akiyama⁵, Nirmala Akula⁶, Martin Alda^{7

8}, Azmeraw T Amare⁹, Raffaella Ardau¹⁰, Bárbara Arias^{11

12}, Jean-Michel Aubry¹³, Lena Backlund¹⁴, Michael Bauer¹⁵, Bernhard T Baune^{9

16}, Frank Bellivier¹⁷, Antonio Benabarre¹⁸, Susanne Bengesser¹⁹, Abesh Kumar Bhattacharjee¹, Joanna M Biernacka^{20

21}, Pablo Cervantes²², Guo-Bo Chen²², Hsi-Chung Chen²³, Caterina Chillotti¹⁰, Sven Cichon^{24

25}, Scott R Clark⁹, Francesc Colom¹⁸, David A Cousins²⁶, Cristiana Cruceanu²⁷, Piotr M Czerski²⁸, Clarissa R Dantas²⁹, Alexandre Dayer¹³, Maria Del Zompo^{10

30}, Franziska Degenhardt²⁴, J Raymond DePaulo³¹, Bruno Étain¹⁷, Peter Falkai³², Frederike Tabea Fellendorf¹⁹, Ewa Ferensztajn-Rochowiak³³, Andreas J Forstner²⁴, Louise Frisén^{14

34

35}, Mark A Frye²¹, Janice M Fullerton^{36

37}, Sébastien Gard³⁸, Julie S Garnham⁷, Fernando S Goes³¹, Maria Grigoroiu-Serbanescu³⁹, Paul Grof⁴⁰, Oliver Gruber⁴¹, Ryota Hashimoto⁴², Joanna Hauser²⁸, Urs Heilbronner³², Stefan Herms^{24

25}, Per Hoffmann^{24

25}, Andrea Hofmann²⁴, Liping Hou⁶, Stephane Jamain⁴³, Esther Jiménez¹⁸, Jean-Pierre Kahn⁴⁴, Layla Kassem⁶, Tadafumi Kato⁴⁵, Sarah Kittel-Schneider⁴⁶, Barbara König⁴⁷, Po-Hsiu Kuo⁴⁸, Ichiro Kusumi⁴⁹, Nina Lackner¹⁹, Gonzalo Laje⁶, Mikael Landén^{50

51}, Catharina Lavebratt¹⁴, Marion Leboyer⁵², Susan G Leckband⁵³, Carlos A López Jaramillo⁵⁴, Glenda MacQueen⁵⁵, Mario Maj⁵⁶, Mirko Manchia^{57

58}, Cynthia Marie-Claire¹⁷, Lina Martinsson⁵⁹, Manuel Mattheisen⁶⁰, Michael J McCarthy⁶¹, Susan L McElroy⁶², Francis J McMahon⁶, Philip B Mitchell⁶³, Marina Mitjans⁶⁴, Francis M Mondimore³¹, Palmiero Monteleone⁶⁵, Caroline M Nievergelt¹, Markus M Nöthen²⁴, Tomas Novák⁸, Urban Ösby⁶⁶, Norio Ozaki⁶⁷, Sergi Papiol⁶⁸, Roy H Perlis⁶⁹, Claudia Pisanu³⁰, James B Potash⁷⁰, Andrea Pfennig¹⁵, Daniela Reich-Erkelenz³², Andreas Reif⁴⁶, Eva Z Reininghaus¹⁹, Marcella Rietschel⁷¹, Guy A Rouleau⁷², Janusz K Rybakowski³³, Martin Schalling¹⁴, Peter R Schofield^{36

37}, K Oliver Schubert⁹, Thomas G Schulze^{6

31

32

41

71}, Barbara W Schweizer³¹, Florian Seemüller³², Giovanni Severino³⁰, Tatyana Shekhtman^{1

73}, Paul D Shilling¹, Kazutaka Shimoda⁷⁴, Christian Simhandl⁷⁵, Claire M Slaney⁷, Alessio Squassina³⁰, Thomas Stamm³, Pavla Stopkova⁸, Sarah K Tighe^{70

76}, Alfonso Tortorella⁵⁶, Gustavo Turecki²⁷, Eduard Vieta¹⁸, Julia Volkert⁴⁶, Stephanie Witt⁷¹, Naomi R Wray⁷⁷, Adam Wright⁶³, L Trevor Young⁷⁸, Peter P Zandi⁷⁹, John R Kelsoe^{80

81}

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
² Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
³ Department of Psychiatry and Psychotherapy, Charité- Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
⁴ Fliedner Klinik Berlin, Center for Psychiatry, Psychotherapy and Psychosomatic Medicine, Berlin, Germany.
⁵ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁶ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
⁷ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
⁸ National Institute of Mental Health, Klecany, Czech Republic.
⁹ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
¹⁰ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹¹ Department of Evolutive Biology, Ecology and Environmental Sciences, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
¹² CIBER de Salud Mental, ISCIII, Madrid, Barcelona, Catalonia, Spain.
¹³ Department of Mental Health and Psychiatry, Mood Disorders Unit-Geneva University Hospitals, Geneva, Switzerland.
¹⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁵ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
¹⁶ Department of Psychiatry, University of Münster, Münster, Germany.
¹⁷ INSERM UMR-S 1144-Université Paris Cité Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Lariboisière-F Widal, Paris, France.
¹⁸ Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, ISCIII, Barcelona, Catalonia, Spain.
¹⁹ Neurobiological Background and Anthropometrics in Bipolar Affective Disorder, Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.
²⁰ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
²¹ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²² The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
²³ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁴ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
²⁵ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁶ Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
²⁷ Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
²⁸ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
²⁹ Department of Psychiatry, University of Campinas (Unicamp), Campinas, Brazil.
³⁰ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³² Institute of Psychiatric Phenomics and Genomics (IPPG) and Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany.
³³ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
³⁴ Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
³⁵ Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
³⁶ Mental Illness Research Theme, Neuroscience Research Australia, Sydney, NSW, Australia.
³⁷ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
³⁸ Pôle de Psychiatrie Générale Universitaire, Centre Hospitalier Charles Perrens, Bordeaux, France.
³⁹ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Bucharest, Romania.
⁴⁰ Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
⁴¹ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁴² Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴³ Inserm U955, Psychiatrie Translationnelle, Créteil, France.
⁴⁴ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy-Laxou-Université de Lorraine, Nancy, France.
⁴⁵ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
⁴⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt-Goethe University, Frankfurt am Main, Germany.
⁴⁷ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁴⁸ Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
⁴⁹ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁵⁰ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵² Assistance Publique-Hôpitaux de Paris, Hôpital Albert Chenevier-Henri Mondor, Pôle de Psychiatrie, Créteil, France.
⁵³ Department of Pharmacy, VA San Diego Healthcare System, La Jolla, CA, USA.
⁵⁴ Department of Psychiatry, University of Antioquia, Medellín, Medellín, Colombia.
⁵⁵ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁵⁶ Department of Psychiatry, University of Naples SUN, Naples, Italy.
⁵⁷ Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁸ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁵⁹ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁶⁰ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁶¹ Department of Psychiatry, VA San Diego Healthcare System, La Jolla, CA, USA.
⁶² Department of Psychiatry, Lindner Center of Hope, University of Cincinnati, Mason, OH, USA.
⁶³ School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia.
⁶⁴ Department of Genetics, Microbiology, and Statistics, Faculty of Biology and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, CIBER de Salud Mental, ISCIII, Madrid, Spain.
⁶⁵ Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁶⁶ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁷ Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁸ Ludwig-Maximilians-University of Munich, Munich, Germany.
⁶⁹ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷⁰ Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
⁷¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁷² Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁷³ Veterans Administration, San Diego Healthcare System, San Diego, CA, USA.
⁷⁴ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁷⁵ Bipolar Center, Wiener Neustadt, Austria.
⁷⁶ University of Iowa Carver College of Medicine and University of Iowa College of Public Health, VA Quality Scholars Program, Iowa City VA Hospital, Iowa City, IA, USA.
⁷⁷ The University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia.
⁷⁸ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁷⁹ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸⁰ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. jkelsoe@health.ucsd.edu.
⁸¹ Veterans Administration, San Diego Healthcare System, San Diego, CA, USA. jkelsoe@health.ucsd.edu.

PMID: 38395906
PMCID: PMC10891068
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 et al. Transl Psychiatry. 2024.

. 2024 Feb 23;14(1):109.

doi: 10.1038/s41398-024-02811-4.

Authors

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
² Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
³ Department of Psychiatry and Psychotherapy, Charité- Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
⁴ Fliedner Klinik Berlin, Center for Psychiatry, Psychotherapy and Psychosomatic Medicine, Berlin, Germany.
⁵ Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁶ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, USA.
⁷ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
⁸ National Institute of Mental Health, Klecany, Czech Republic.
⁹ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
¹⁰ Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
¹¹ Department of Evolutive Biology, Ecology and Environmental Sciences, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
¹² CIBER de Salud Mental, ISCIII, Madrid, Barcelona, Catalonia, Spain.
¹³ Department of Mental Health and Psychiatry, Mood Disorders Unit-Geneva University Hospitals, Geneva, Switzerland.
¹⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹⁵ Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
¹⁶ Department of Psychiatry, University of Münster, Münster, Germany.
¹⁷ INSERM UMR-S 1144-Université Paris Cité Département de Psychiatrie et de Médecine Addictologique, AP-HP, Groupe Hospitalier Lariboisière-F Widal, Paris, France.
¹⁸ Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, ISCIII, Barcelona, Catalonia, Spain.
¹⁹ Neurobiological Background and Anthropometrics in Bipolar Affective Disorder, Division of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.
²⁰ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
²¹ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
²² The Neuromodulation Unit, McGill University Health Centre, Montreal, QC, Canada.
²³ Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.
²⁴ Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.
²⁵ Human Genomics Research Group, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁶ Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
²⁷ Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
²⁸ Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
²⁹ Department of Psychiatry, University of Campinas (Unicamp), Campinas, Brazil.
³⁰ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
³² Institute of Psychiatric Phenomics and Genomics (IPPG) and Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany.
³³ Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
³⁴ Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
³⁵ Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
³⁶ Mental Illness Research Theme, Neuroscience Research Australia, Sydney, NSW, Australia.
³⁷ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
³⁸ Pôle de Psychiatrie Générale Universitaire, Centre Hospitalier Charles Perrens, Bordeaux, France.
³⁹ Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Bucharest, Romania.
⁴⁰ Mood Disorders Center of Ottawa, Ottawa, ON, Canada.
⁴¹ Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
⁴² Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
⁴³ Inserm U955, Psychiatrie Translationnelle, Créteil, France.
⁴⁴ Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy-Laxou-Université de Lorraine, Nancy, France.
⁴⁵ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
⁴⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt-Goethe University, Frankfurt am Main, Germany.
⁴⁷ Department of Psychiatry and Psychotherapeutic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
⁴⁸ Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
⁴⁹ Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁵⁰ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, Gothenburg, Sweden.
⁵¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵² Assistance Publique-Hôpitaux de Paris, Hôpital Albert Chenevier-Henri Mondor, Pôle de Psychiatrie, Créteil, France.
⁵³ Department of Pharmacy, VA San Diego Healthcare System, La Jolla, CA, USA.
⁵⁴ Department of Psychiatry, University of Antioquia, Medellín, Medellín, Colombia.
⁵⁵ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁵⁶ Department of Psychiatry, University of Naples SUN, Naples, Italy.
⁵⁷ Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
⁵⁸ Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
⁵⁹ Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
⁶⁰ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁶¹ Department of Psychiatry, VA San Diego Healthcare System, La Jolla, CA, USA.
⁶² Department of Psychiatry, Lindner Center of Hope, University of Cincinnati, Mason, OH, USA.
⁶³ School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, NSW, Australia.
⁶⁴ Department of Genetics, Microbiology, and Statistics, Faculty of Biology and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, CIBER de Salud Mental, ISCIII, Madrid, Spain.
⁶⁵ Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
⁶⁶ Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁶⁷ Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶⁸ Ludwig-Maximilians-University of Munich, Munich, Germany.
⁶⁹ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷⁰ Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
⁷¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁷² Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁷³ Veterans Administration, San Diego Healthcare System, San Diego, CA, USA.
⁷⁴ Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan.
⁷⁵ Bipolar Center, Wiener Neustadt, Austria.
⁷⁶ University of Iowa Carver College of Medicine and University of Iowa College of Public Health, VA Quality Scholars Program, Iowa City VA Hospital, Iowa City, IA, USA.
⁷⁷ The University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia.
⁷⁸ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁷⁹ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸⁰ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. jkelsoe@health.ucsd.edu.
⁸¹ Veterans Administration, San Diego Healthcare System, San Diego, CA, USA. jkelsoe@health.ucsd.edu.

PMID: 38395906
PMCID: PMC10891068
DOI: 10.1038/s41398-024-02811-4

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.

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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, Pfizer Japan, 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, Pfizer, 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. MMan 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

**Fig. 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.

**Fig. 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.

**Fig. 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

Update of

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.
Kelsoe J, Ou A, Rosenthal S, Adli M, Akiyama K, Akula N, Alda M, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Banzato C, Bauer M, Baune B, Bellivier F, Benabarre A, Bengesser S, Abesh B, Biernacka J, Bui E, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark S, Colom F, Cousins D, Cruceanu C, Czerski P, Dantas C, Dayer A, Degenhardt F, DePaulo JR, Etain B, Falkai P, Fellendorf F, Ferensztajn-Rochowiak E, Forstner AJ, Frisen L, Frye M, Fullerton J, Gard S, Garnham J, Goes F, 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, Dalkner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband S, Jaramillo CL, MacQueen G, Maj M, Manchia M, Marie-Claire C, Martinsson L, Mattheisen M, McCarthy M, McElroy S, McMahon F, Mitchell P, Mitjans M, Mondimore F, Monteleone P, Nievergelt C, Nöthen M, Novak T, Osby U, Ozaki N, Papiol S, Perlis R, Pfennig A, Potash J, Reich-Erkelenz D, Reif A, Reininghaus E, Rietschel M, Rouleau G, Rybakowski JK, Schalling M, Schofield P, Schubert KO, Schulze T, Schweizer B, Seemüller F, Severino … See abstract for full author list ➔ Kelsoe J, et al. Res Sq [Preprint]. 2023 Oct 3:rs.3.rs-3258813. doi: 10.21203/rs.3.rs-3258813/v1. Res Sq. 2023. Update in: Transl Psychiatry. 2024 Feb 23;14(1):109. doi: 10.1038/s41398-024-02811-4. PMID: 37886563 Free PMC article. Updated. Preprint.

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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

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