Brain morphology mediators of the link between childhood trauma and bipolar disorder: a large-scale international analysis

Leonardo Tozzi; Maria R. Dauvermann; Emma Corley; Andrea Fernandes; Melody J. Y. Kang; Yanghee Im; Leila Nabulsi; Roberto Goya-Maldonado; Klaus Berger; Marco Hermesdorf; Hilary P. Blumberg; Lejla Colic; Tamsyn E. Van Rheenen; Elysha Ringin; Susan L. Rossell; James A. Karantonis; Lisa S. Furlong; Tilo Kircher; Frederike Stein; Udo Dannlowski; Dominik Grotegerd; Jair C. Soares; Mon-Ju Wu; Giovana B. Zunta-Soares; Benson Mwangi; Joaquim Radua; Enric Vilajosana; Eduard Vieta; Melissa J. Green; Emilie Olie; Guillaume Clain; Francesco Benedetti; Elisa Melloni; Beatrice Bravi; Delfina Janiri; Daniela Vecchio; Fabrizio Piras; Nerisa Banaj; Gabriele Sani; Gloria Roberts; Janice M. Fullerton; Bronwyn J. Overs; Philip B. Mitchell; Jonathan Savitz; Lakshmi N. Yatham; Josselin Houenou; Marion Leboyer; Amanda Rodrigue; David C. Glahn; Sophia I. Thomopoulos; Neda Jahanshad; Paul M. Thompson; Ole A. Andreassen; Christopher R. K. Ching; Dara M. Cannon; Yann Quidé; ENIGMA Bipolar Disorder Working Group

doi:10.1101/2025.11.02.25339336

Prépublication

Brain morphology mediators of the link between childhood trauma and bipolar disorder: a large-scale international analysis

Leonardo Tozzi, Maria R. Dauvermann, Emma Corley, Andrea Fernandes, Melody J. Y. Kang, Yanghee Im, Leila Nabulsi, Roberto Goya-Maldonado, Klaus Berger, Marco Hermesdorf, …

medRxiv

Cold Spring Harbor Laboratory Press, 1.1

04/11/2025

DOI: https://doi.org/10.1101/2025.11.02.25339336

PMID: 41282728

Résumé

Psychiatry and Clinical Psychology

Childhood trauma is a risk factor for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association between childhood trauma and bipolar disorder might be mediated through brain morphology. Our goal was to determine whether cortical thickness, cortical surface or subcortical volume mediate the association between childhood trauma and bipolar disorder. We leveraged a large multi-site dataset from the ENIGMA Bipolar Disorder Working Group, comprising of 1,031 participants with bipolar disorder and 2,221 controls from 19 international cohorts. To identify brain morphology mediators of the association of childhood trauma and bipolar disorder, we used high-dimensional mediation analysis and validated our results using leave-one-site-out cross-validation and permutation testing for significance. Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient 0.841, 95% CI: [0.834, 0.851], p<0.001). Significant mediators were hippocampal volume (0.004, 95% CI: [0.002, 0.005], p<0.001), medial orbitofrontal gray matter thickness (0.002, 95% CI: [0.002, 0.003], p<0.001), and superior frontal gyrus gray matter thickness (0.002, 95% CI: [0, 0.005], p<0.001). Our results show that the severity of childhood trauma exposure is associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves our etiologic understanding of bipolar disorder and could help to identify those at risk and enable the development of new interventions.

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Détails

Titre: Brain morphology mediators of the link between childhood trauma and bipolar disorder: a large-scale international analysis
Créateurs - sans rôle: Leonardo Tozzi - Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine
Maria R. Dauvermann - University of Birmingham
Emma Corley - Clinical Neuroimaging Laboratory, Galway Neuroscience Center, College of Medicine, Nursing and Health Sciences, University of Galway
Andrea Fernandes - Clinical Neuroimaging Laboratory, Galway Neuroscience Center, College of Medicine, Nursing and Health Sciences, University of Galway
Melody J. Y. Kang - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Yanghee Im - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Leila Nabulsi - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Roberto Goya-Maldonado - Laboratory of Systems Neuroscience and Imaging in Psychiatry (SNIP-Lab), Department of Psychiatry and Psychotherapy, University Medical Center Göttingen
Klaus Berger - University of Münster
Marco Hermesdorf - University of Münster
Hilary P. Blumberg - Yale School of Medicine
Lejla Colic - German Center for Mental Health (DZPG)
Tamsyn E. Van Rheenen - Center for Mental Health and Brain Sciences, Swinburne University
Elysha Ringin - Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
Susan L. Rossell - Center for Mental Health and Brain Sciences, Swinburne University
James A. Karantonis - Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
Lisa S. Furlong - Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne
Tilo Kircher - Department of Psychiatry and Psychotherapy, Marburg University
Frederike Stein - Department of Psychiatry and Psychotherapy, Marburg University
Udo Dannlowski - Bielefeld University
Dominik Grotegerd - University of Münster
Jair C. Soares - The University of Texas Health Science Center at Houston
Mon-Ju Wu - The University of Texas Health Science Center at Houston
Giovana B. Zunta-Soares - The University of Texas Health Science Center at Houston
Benson Mwangi - The University of Texas Health Science Center at Houston
Joaquim Radua - IDIBAPS, Hospital Clinic Barcelona, CIBERSAM–Instituto de Salud Carlos III, Institute of Neuroscience, Universitat de Barcelona
Enric Vilajosana - IDIBAPS, Hospital Clinic Barcelona, CIBERSAM–Instituto de Salud Carlos III, Institute of Neuroscience, Universitat de Barcelona
Eduard Vieta - Instituto de Salud Carlos III
Melissa J. Green - School of Clinical Medicine, The University of New South Wales (UNSW) Sydney
Emilie Olie - IGF, University of Montpellier
Guillaume Clain - Institut d’Imagerie Fonctionnelle Humaine, Platform I2FH, Department of Neuroradiology, University Hospital of Montpellier
Francesco Benedetti - University Vita-Salute San Raffaele
Elisa Melloni - Psychiatry & Clinical Psychobiology, Division of Neuroscience
Beatrice Bravi - Psychiatry & Clinical Psychobiology, Division of Neuroscience
Delfina Janiri - Department of Neuroscience, Section of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Daniela Vecchio - Neuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS
Fabrizio Piras - Neuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS
Nerisa Banaj - Neuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS
Gabriele Sani - Department of Neuroscience, Section of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Gloria Roberts - School of Clinical Medicine, The University of New South Wales (UNSW) Sydney
Janice M. Fullerton - Neuroscience Research Australia
Bronwyn J. Overs - Neuroscience Research Australia
Philip B. Mitchell - UNSW Sydney
Jonathan Savitz - Laureate Institute for Brain Research
Lakshmi N. Yatham - Department of Psychiatry, University of British Columbia
Josselin Houenou - Mental Health Services
Marion Leboyer - INSERM U955 Team “Translational Neuropsychiatry,” Université Paris-Est Créteil
Amanda Rodrigue - Department of Psychiatry, Boston Children’s Hospital, Harvard Medical School
David C. Glahn - Boston Children's Hospital
Sophia I. Thomopoulos - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Neda Jahanshad - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Paul M. Thompson - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Ole A. Andreassen - Center for Precision Psychiatry, University of Oslo, Oslo University Hospital
Christopher R. K. Ching - Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California
Dara M. Cannon - Ollscoil na Gaillimhe – University of Galway
Yann Quidé - Center for Pain IMPACT, Neuroscience Research Australia
ENIGMA Bipolar Disorder Working Group
Détails de publication: medRxiv
Éditeur: Cold Spring Harbor Laboratory Press
Édition: 1.1
Nombre de pages: 26
Identifiants: 99139501709311
Unité académique: Institut de Génomique Fonctionnelle - IGF
Langue: English
Type de ressource: Preprint