ArticleResearch square2023
Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.
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Authors and funding
126 authors at 20 institutions in 14 countries.
John KelsoeUniversity of California San Diego.
Anna OuUniversity of California San Diego.ORCID 0009-0006-0714-1684
Sara Rosenthal
Mazda Adli
Kazufumi AkiyamaDepartment of Biological Psychiatry and Neuroscience, Dokkyo Medical University.
Nirmala AkulaNational Institutes of Health, US Dept of Health & Human Services.
Martin AldaDalhousie University.ORCID 0000-0001-9544-3944
Azmeraw T AmareUniversity of Adelaide, AUSTRALIA.ORCID 0000-0002-7940-0335
Raffaella ArdauHospital University Agency of Cagliari.
Bárbara AriasFacultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM.ORCID 0000-0001-9181-2132
Jean-Michel AubryGeneva University Hospitals.
Lena Backlund
Claudio Banzato
Michael BauerUniversity Hospital Carl Gustav Carus.ORCID 0000-0002-2666-859X
Bernhard BauneUniversity of Münster.ORCID 0000-0001-6548-426X
Frank Bellivier
Antonio Benabarre
Susanne Bengesser
Bhattacharjee Abesh
Joanna BiernackaMayo Clinic.ORCID 0000-0001-9350-4440
Elise Bui
Pablo CervantesMcGill University Health Centre.
Guo-Bo Chen
Hsi-Chung Chen3Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan 4Department of Psychiatry, Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.ORCID 0000-0003-3191-0093
Caterina Chillotti
Sven CichonMayo Clinic.
Scott ClarkUniversity of Adelaide.ORCID 0000-0003-1640-5611
Francesc Colom
David Cousins
Cristiana CruceanuMax Plank Institute for Psychiatry.ORCID 0000-0002-7799-5531
Piotr CzerskiPoznan University of Medical Sciences.ORCID 0000-0003-0745-5916
Clarissa Dantas
Alexandre DayerUniversity of Geneva.
Franziska DegenhardtUniversity of Essen.
J Raymond DePauloJohns Hopkins University.ORCID 0000-0001-9221-9226
Bruno EtainORCID 0000-0002-5377-1488
Peter FalkaiUniversity Hospital LMU.
Frederike Fellendorf
Ewa Ferensztajn-Rochowiak
Andreas J ForstnerUniversity of Bonn, School of Medicine & University Hospital Bonn.ORCID 0000-0002-1876-6368
Louise FrisenSchool of Medicine & University Hospital Bonn.
Mark FryeMayo Clinic.ORCID 0000-0001-6997-4215
Janice FullertonNeuroscience Research Australia.ORCID 0000-0003-4014-4490
Sebastien Gard
Julie GarnhamORCID 0000-0002-7987-4995
Fernando Goes
Maria Grigoroiu-SerbanescuAlexandru Obregia Clinical Psychiatric Hospital.ORCID 0000-0002-1304-6687
Paul Grof
Oliver Gruber
Ryota HashimotoNational Center of Neurology and Psychiatry.ORCID 0000-0002-5941-4238
Joanna HauserORCID 0000-0002-6621-3493
Urs HeilbronnerInstitute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich.ORCID 0000-0001-7135-762X
Stefan Herms
Per HoffmannInstitute of Human Genetics.
Andrea Hofmann
Liping HouNational Institute of Mental Health Intramural Research Program, National Institutes of Health.ORCID 0000-0003-3972-245X
Stéphane JamainUniv Paris Est Creteil, INSERM, IMRB.ORCID 0000-0002-4321-4100
Esther Jiménez
Jean-Pierre Kahn
Layla KassemSchool of Medicine & University Hospital Bonn.
Tadafumi KatoJuntendo University Graduate School of Medicine.ORCID 0000-0001-7856-3952
Sarah Kittel-Schneider
Barbara König
Po-Hsiu KuoCollege of Public Health, National Taiwan University, Taipei, Taiwan.ORCID 0000-0003-0365-3587
Ichiro KusumiHokkaido University Graduate School of Medicine.ORCID 0000-0002-8747-5070
Nina Dalkner
Gonzalo Laje
Mikael LandénGothenburg University.ORCID 0000-0002-4496-6451
Catharina LavebrattKarolinska Institutet.ORCID 0000-0003-4987-2718
Marion LeboyerORCID 0000-0001-5473-3697
Susan Leckband
Carlos López Jaramillo
Glenda MacQueen
Mario MajUniversity of Naples, Italy.
Mirko ManchiaDalhousie University.
Cynthia Marie-ClaireINSERM UMR-S 1144.ORCID 0000-0002-2282-134X
Lina MartinssonKarolinska Institutet.
Manuel MattheisenJohns Hopkins University.
Michael McCarthy
Susan McElroyLindner Center.
Francis McMahonNational Institute of Mental Health Intramural Research Program; National Institutes of Health.ORCID 0000-0002-9469-305X
Philip MitchellUniversity of New South Wales.ORCID 0000-0002-7954-5235
Marina MitjansMax Planck Institute of Experimental Medicine, Göttingen, Germany.ORCID 0000-0001-5543-7320
Francis MondimoreNeuroscience Research Australia.
Palmiero MonteleoneUniversity of Salerno, University of Naples SUN.
Caroline NievergeltUniversity of California, San Diego.ORCID 0000-0001-5766-8923
Markus NöthenSchool of Medicine & University Hospital Bonn.ORCID 0000-0002-8770-2464
Tomas NovakNational Institute of Mental Health, Klecany.ORCID 0000-0001-9156-9654
Urban OsbyKarolinska Institutet.
Norio OzakiNagoya University.ORCID 0000-0002-7360-4898
Sergi PapiolUniversity Hospital LMU.ORCID 0000-0001-9366-8728
Roy PerlisMassachusetts General Hospital.
Andrea PfennigUniversity Hospital Carl Gustav Carus, TU Dresden.
James Potash
Daniela Reich-Erkelenz
Andreas ReifUniversity Hospital Frankfurt, Germany.ORCID 0000-0002-0992-634X
Eva ReininghausORCID 0000-0001-5964-4087
Marcella RietschelUniversity of Mannheim.ORCID 0000-0002-5236-6149
Guy RouleauMcGill University.ORCID 0000-0001-8403-1418
Janusz K RybakowskiPoznan University of Medical Sciences.ORCID 0000-0003-0577-0381
Martin SchallingKarolinska Institutet.ORCID 0000-0001-5011-2922
Peter SchofieldNeuroscience Research Australia.ORCID 0000-0003-2967-9662
Klaus Oliver SchubertUniversity of Adelaide.ORCID 0000-0003-1690-0209
Thomas SchulzeUniversity of Munich.ORCID 0000-0001-6624-2975
Barbara Schweizer
Florian Seemüller
Giovanni SeverinoUniversity of Cagliari.ORCID 0000-0002-6354-2662
Tatyana Shekhtman
Paul ShillingORCID 0000-0002-0129-5504
Kazutaka ShimodaORCID 0000-0002-9663-6243
Christian Simhandl
Claire Slaney
Alessio SquassinaUniversita degli Studi Di Cagliari.ORCID 0000-0001-7415-7607
Thomas StammCharité - Universitätsmedizin Berlin, Campus Charité Mitte.
Pavla Stopkova
Sarah Tighe
Alfonso TortorellaDepartment of Psychiatry, University of Perugia, Perugia, Italy.
Gustavo TureckiDouglas Institute, Department of Psychiatry, McGill University.ORCID 0000-0003-4075-2736
Eduard VietaHospital Clinic of Barcelona.ORCID 0000-0002-0548-0053
Julia Volkert
Stephanie WittUniversity Medical Centre Mannheim.ORCID 0000-0002-1571-1468
Naomi WrayUniversity of Queensland.ORCID 0000-0001-7421-3357
Adam Wright
Trevor Young
Peter ZandiJohns Hopkins University.
Maria Del ZompoUniversity of Cagliari.ORCID 0000-0001-9491-5938
Karolinska Institutet · SEJohns Hopkins University · USNeuroscience Research Australia · AUThe University of Adelaide · AUUniversity of Cagliari · ITUniversity of California San Diego · USWinnMed · USDalhousie University · CAInserm · FRNational Institute of Mental Health · JPPoznan University of Medical Sciences · PLUniversity Hospital Carl Gustav Carus · DECentro de Investigación Biomédica en Red de Salud Mental · ESCharité - Universitätsmedizin Berlin · DEDokkyo Medical University · JPDouglas Mental Health University Institute · CAGeneva College · USGoethe University Frankfurt · DEHokkaido University · JPHospital Clínic de Barcelona · ES
Funding
The Collaborative Genetic Study of Nicotine DependenceP01CA089392 · NCI · WASHINGTON UNIVERSITY · PI BIERUT, LAURA J. · 2001 to 2012
$17.3MPharmacogenomics of Mood Stabilizer Response in Bipolar DisorderU01MH092758 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KELSOE, JOHN R. · 2010 to 2014
$6.2MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH059534 · NIMH · WASHINGTON UNIVERSITY · PI RICE, JOHN P. · 1998 to 2007
$3.1MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH059545 · NIMH · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI NURNBERGER, JOHN I · 1998 to 2007
$2.6MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH059533 · NIMH · JOHNS HOPKINS UNIVERSITY · PI MACKINNON, DEAN FREDERICK · 1998 to 2007
$2.4MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH060068 · NIMH · UNIVERSITY OF CALIFORNIA IRVINE · PI BYERLEY, WILLIAM · 1998 to 2007
$2.1MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH059553 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI BERRETTINI, WADE H · 1998 to 2007
$2.1MMapping genes that contribute to bipolar disorderZ01MH002810 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI MCMAHON, FRANCIS J · 2003 to 2008
$2.0MCollaborative Genomic Study of Bipolar DisorderR01MH059548 · NIMH · UNIVERSITY OF IOWA · PI CORYELL, WILLIAM HENRY · 1998 to 2007
$1.9MCOLLABORATIVE STUDY OF BIPOLAR DISORDERR01MH059535 · NIMH · UNIVERSITY OF CHICAGO · PI GERSHON, ELLIOT S · 1998 to 2007
$1.9MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH059567 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KELSOE, JOHN R. · 1998 to 2007
$1.8MCOLLABORATIVE GENOMIC STUDY OF BIPOLAR DISORDERR01MH059556 · NIMH · RUSH UNIVERSITY MEDICAL CENTER · PI SCHEFTNER, WILLIAM A · 1998 to 2007
$1.6MIntramural NIH HHS Z01 MH002810Medical Research Council MR/L006642/1NCI NIH HHS P01 CA089392NIDA NIH HHS K02 DA021237NIMH NIH HHS R01 MH059533NIMH NIH HHS R01 MH059534NIMH NIH HHS R01 MH059535NIMH NIH HHS R01 MH059545NIMH NIH HHS R01 MH059548NIMH NIH HHS R01 MH059553NIMH NIH HHS R01 MH059556NIMH NIH HHS R01 MH059567NIMH NIH HHS R01 MH060068NIMH NIH HHS U01 MH092758
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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