An Imaging Risk Score for Bipolar Disorder: Multimodal Comparison and Integration with Polygenic Risk
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Summary Background Biological risk scores provide objective markers of bipolar disorder (BD) liability. Large-scale genome-wide association studies (GWASs) have led to polygenic risk scores (PRSs) that capture genetic liability to BD at the individual level. We lack a comparable large-scale effort to leverage a brain-wide association study (BWAS) to create an imaging risk score (IRS) that captures brain structural liability to BD at the individual-level. Here, we conduct the largest multivariate BWAS of BD and develop a BD IRS. We compare the BD IRS to the PRS and assess their combined predictive performance in multimodal risk score (MRS) models. Methods Our multivariate BD BWAS used 153 structural neuroimaging features from 3902 cases and 6855 controls (mean age (sd)=35.47 years (13.42), 56.70% female) in a cross-validated machine learning approach. Using the resulting model coefficients, we constructed an IRS. We then evaluated the out-of-sample performance of the IRS, PRS derived from the largest GWAS to date, and combined MRS model using logistic regression in a subset of individuals with imaging and genetic data (n BD =486, n controls =1701, age (sd)=33.10 (12.02), 56.47% female). We also performed stratified analyses for demographic and BD clinical groups. Prediction performance was quantified using the area under the receiver operating characteristic curve (AUC). Subsequent analyses examined associations between each risk score and BD relevant symptoms in developing youth. Outcomes In predicting case status, the BD BWAS model achieved a mean AUC BD of 0.62 (sd BD =0.08) and in stratified analyses, had higher prediction than subgroup-specific BWAS models. The BD type II BWAS was the only exception (AUC BDII =0.60, sd BDII =0.07 vs AUC BD =0.58, sd BD =0.09). The BD PRS had an AUC BD of 0.65 (CI 95% =0.63-0.68) and a higher AUC than subtype-specific PRS in stratified analyses. The PRS typically attained a higher AUC than the IRS. Notably, the IRS and PRS were uncorrelated (r=0.03, p=0.11). MRS models outperformed the prediction of individual PRS and IRS with the strongest prediction for BD type I (AUC BD =0.74, CI 95% =0.70-0.78). The IRS had the strongest associations with BD-related symptoms in developing youth including increased energy (OR=1.21, p fdr =0.03) and distress from psychotic-like experiences (OR=1.23, p fdr =0.04). Interpretation Our BD IRS is a novel biological indicator of BD risk. The lack of correlation between the IRS and PRS along with improved MRS prediction suggests the two risk scores capture some orthogonal liability to BD. We show that integrating imaging and genetics is useful for biological characterization of BD and should be considered for the development of clinically relevant prediction models.
Source: medRxiv
Authors: Nadine Parker, Kevin S. O’Connell, Alexey A. Shadrin, Pravesh Parekh, Melody J.Y. Kang, Jakub Kopal, Espen Hagen, Kody G. Kennedy, Yanghee Im, Dag Alnæs, Dylan Hughes, Martin Alda, Nina Alexander, Luisa Altegoer, Ana Aquino-Servín, Jochen Bauer, Dunya Bedir, Francesco Benedetti, Klaus Berger, Michael Berk, Hilary P. Blumberg, Tiana Borgers, Kiymet Bozaoglu, Beatrice Bravi, Geraldo F. Busatto, Erick Jorge Canales, Dara M. Cannon, Xavier Caseras, I-Jou Chi, Paola Fuentes Claramonte, Brett Clementz, Lejla Colic, Emma Corley, Orwa Dandash, Udo Dannlowski, Caroline Demro, Ana M. Díaz-Zuluaga, Karolin Einenkel-Brand, Torbjørn Elvsåshagen, Lisa T. Eyler, Pauline Favre, Kira Flinkenflügel, Maria F. Forte, Janice M. Fullerton, Serena Furno, Gabriel R. Fries, Elliot Gershon, David C. Glahn, Ian H. Gotlib, Roberto Goya-Maldonado, Melissa Green, Dominik Grotegerd, Oliver Gruber, Bartholomeus Haarman, Tim Hahn, Tomas Hajek, Marco Hermesdorf, Josselin Houenou, Fleur M. Howells, Elena I. Ivleva, Hamidreza Jamalabadi, Delfina Janiri, Andreas Jansen, Nooshin Javaheripour, Sarah Keedy, Matthew Kempton, Matcheri Keshavan, Tilo Kircher, Luisa Klahn, Bernd Kraemer, Aodan Laighneach, Mikael Landén, Younghwa Lee, Carlos Lopez-Jaramillo, Walid Makhoul, Ulrik F. Malt, Colm McDonald, Sean McWhinney, Susanne L. Meinert, Philip B. Mitchell, Benson Mwangi, Igor Nenadic, Emilie Olie, Daniele Olivo, Sara Papenbrock, David Parker, Godfrey Pearlson, Fabrizio Piras, Federica Piras, Sara Poletti, Edith Pomarol-Clotet, James Prisciandaro, Yann Quidé, Joaquim Radua, Lisa Rauer, Wiebke Ringels, Elysha Ringin, Gloria Roberts, Amanda L. Rodrigue, Pedro G.P. Rosa, Susan Rossell, Matthew D. Sacchet, Raymond Salvador, Fabio Sambataro, Gabriele Sani, Salvador Sarró, Theodore Satterthwaite, Jonathan Savitz, Freda Scheffler, Maria Serra-Navarro, Yvette I. Sheline, Kang Sim, Jair C. Soares, Márcio Gerhardt Soeiro-de-Souza, Scott Sponheim, Dan J. Stein, Frederike Stein, Benjamin Straube, Carol Tamminga, Henk S. Temmingh, Lea Teutenberg, Florian Thomas-Odenthal, Natasha Topolski, Snezana Urosevic, Paula Usemann, Benedetta Vai, Johanna Valencia-Echeverry, Tamsyn E Van Rheenen, Daniela Vecchio, Eduard Vieta, Enric Vilajosana, Daniel Wolf, Mon-Ju Wu, Albert Yang, Lakshmi Yatham, Marcus V. Zanetti, Giovana B. Zunta-Soares, Carrie E Bearden, Benjamin I. Goldstein, Tobias Kaufmann, Lars T. Westlye, Paul M. Thompson, Anders M. Dale, Christopher R. K. Ching, Ole A. Andreassen
Institutions: Oslo University Hospital, University of Oslo, J. Craig Venter Institute, University of Southern California, Centre for Addiction and Mental Health, University of California, Los Angeles, Dalhousie University, Philipps University of Marburg, University of Münster, Centro de Investigación Biomédica en Red de Salud Mental, Fidmag Sisters Hospitallers, IRCCS Ospedale San Raffaele, Barwon Health, Deakin University, Yale University, Murdoch Children's Research Institute, Universidade de São Paulo, Ollscoil na Gaillimhe – University of Galway, Cardiff University, Kaohsiung Medical University, Universitat Jaume I, University of Georgia, Jena University Hospital, Deutsches Zentrum für Psychische Gesundheit, The University of Melbourne, Austin Health, Bielefeld University, University of Minnesota, Universidad de Antioquia, University Hospital Heidelberg, University of California San Diego, Inserm, Université Paris-Est Créteil, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CEA Paris-Saclay, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, UNSW Sydney, Swinburne University of Technology, The University of Texas Health Science Center at Houston, University of Chicago, Boston Children's Hospital, Harvard University, Stanford University, Universitätsmedizin Göttingen, University Medical Center Groningen, Northern Hospital, Hôpitaux Universitaires Henri-Mondor, University of Cape Town, The University of Texas Southwestern Medical Center, Università Cattolica del Sacro Cuore, Agostino Gemelli University Polyclinic, Istituti di Ricovero e Cura a Carattere Scientifico, King's College London, Beth Israel Deaconess Medical Center, University of Gothenburg, Karolinska Institutet, University of Pennsylvania, Hôpital Lapeyronie, University of Padua, Emory University, Fondazione Santa Lucia, Medical University of South Carolina, Neuroscience Research Australia, Instituto de Salud Carlos III, Laureate Institute for Brain Research, National University of Singapore, Nanyang Technological University, Institute of Mental Health, Minneapolis VA Health Care System, Minneapolis VA Medical Center, South African Medical Research Council, Valkenberg Hospital, National Yang Ming Chiao Tung University, Taipei Veterans General Hospital, University of British Columbia, Hospital Sírio-Libanês, University of Tübingen
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Ministerio de Ciencia, Tecnología e Innovación, U.S. Department of Veterans Affairs, Medical University of South Carolina, John S. Dunn Foundation, Fondation de l'Avenir pour la Recherche Médicale Appliquée, National Alliance for Research on Schizophrenia and Depression, National Imaging Facility, European Commission, South African Medical Research Council, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Stiftelsen för Strategisk Forskning, University of New South Wales, Swinburne University of Technology, Fundação de Amparo à Pesquisa do Estado de São Paulo, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, University of Toronto, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Hjärnfonden, Vetenskapsrådet, NordForsk, Westfälische Wilhelms-Universität Münster, Universidad de Antioquia, Norges Forskningsråd, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, National Health and Medical Research Council, Instituto de Salud Carlos III, Division of Research Capacity Development, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke, National Bioscience Database Center, NextGenerationEU
Awards: G1019437197, G1131686175, G1154649974, G1183304924, G1216156242, G1237346504, G1244514984, G1259338819, G1355063053, G1372999777, G1394621030, G1423865221, G1438067556, G1562954703, G1568777047, Modern Signal Processing Methods for Ultra-realistic Light-Field Displays, G1626468546, G1742417065, G1792323633, G179444772, G1845626873, G2003922037, G2108489402, G2150354811, G2198220640, G222496000, G2302581481, G2357976963, G238323396, G2420318690, G2470823256, G2511155013, G2541994575, G2546134456, G2607375178, G268165469, G2702269330, G2747739348, G2782475662, G2844825193, G298833120, G3002994357, G3097150369, G3157175920, G3166945029, G3170205421, G3209964233, G3265249946, G3434867832, G346361644, G3466994368, G365003729, Skräddarsy psykiatrisk behandling med genomvid kartläggning, G3759917100, G3765340865, G377074410, G378850153, G3903948177, G398641320, G3992405086, G4024195125, G4089841571, G4142848390, G4196154960, Die bidirektionale Analyse der Beziehung zwischen subklinischer Arteriosklerose und der Depression (BiDirect), Influence of Psychosis on Brain-Behavior Endophenotypes for Bipolar Disorder, G4385589004, G4519315536, G4587673340, G4588023527, Searching for Endophenotypes of Bipolar Disorder, G4680818468, Aging and Emotion Regulation Brain Circuitry in Bipolar Disorder, G4812287033, G4874941962, G4902183580, G4914386182, G4984003468, G5030363304, G5052612295, G5061896360, Neural Disconnection and Errant Visual Perception in Psychotic Psychopathology, G5143647079, G5156340569, G5275296542, G540810554, G5417235735, G5479941350, G5485744021, Improving outcomes for youth at risk of bipolar disorder, G5654507885, G5663989965, G5723270564, Biomarkers of Suicide Risk in Adolescents and Young Adults: Factors that Con, G5885064267, G593126264, Carving psychosis at its biological joints, G6085389302, G6105316060, G6124099276, G6125999700, Gene Networks Influencing Psychotic Dysconnectivity in African Americans, G6176481762, G6188346138, G6274528536, G6373421114, G646156818, G6486808345, G648958512, G6531169715, G6531811719, G656100070, G6571705648, G6653174320, Sorbonne Universités à Paris pour l'Enseignement et la Recherche, G6711482573, G6711686236, G6716766040, G6728725779, G6733821374, G67759314, G678574272, G6858926394, G6899542990, Leveraging Nordic Opportunities to Transform Mental Health Care through Precision Medicine (PreciMENT), G6967829241, Predicting comorbid cardiovascular disease in individuals with mental disorder by decoding disease mechanisms, Analyse der Beziehung zwischen subklinischer Arteriosklerose und der Depression (BiDirect) (Anschlussvorhaben), G7119240494, G7166423909, G7181694704, G7190904907, G7212429703, G7233576643, G727061632, G727798130, G7341669135, G7398309870, Neuroimaging mechanisms of overlap between alcoholism and bipolar disorder, Improving our understanding of hearing voices, G7497706539, G752819877, G7746733964, G7780819509, G780302099, G7867085277, G792334296, G7984825499, Yale University Clinical and Translational Science Award Program, G8087705, G8132297629, G8213999919, Development of Brain Abnormalities in Bipolar Disorder, G8259830708, G8397336999, Brain Emotion Circuitry-Targeted Self-Monitoring and Regulation Therapy (BE-SMART), G8486495155, DZPG Ausbauförderung - VISIONS1 - Partner Uniklinik Jena, Depressive and bipolar disorders: Causes, presentation and treatment innovations, G8606111478, 3/5 Bipolar-Schizophrenia Network for Intermediate Phenotypes 2 (BSNIP-2), G8684370047, Genetic Influences on Frontotemporal Connectivity in Bipolar Disorder, G9000280126, Understanding Rare Genetic Variation and Disease Risk: A Global Neurogenetics Initiative, 20/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT VCU, 3/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT U MINNESOTA, 4/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT FIU, 7/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT YALE, 15/21 ABCD-USA Consortium: Research Project Site at LIBR, 16/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT UNIVERSITY OF ROCHESTER, ABCD-USA Consortium: Coordinating Center, 10/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT SRI, 12/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT U PITTSBURGH, 19/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT UVM, 1/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT U UTAH, Genetic Risk for Serious Mental Illness and Development, ENIGMA Bipolar Initiative: A Global Study of Imaging Genomics & Clinical Outcomes, 11/21 ABCD-USA Consortium: Research Project Site at UWM, Psychobiological Mechanisms Underlying the Association Between Early Life Stress and Depression Across Adolescence, Training Grant in Neurobehavioral Genetics, A Latin American biobank for large-scale genetics research on severe mental illness, ABCD-USA Consortium: Data Analysis, Informatics and Resource Center, 13/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT MUSC, 5/21 ABCD-USA Consortium: Research Project Site at UC San Diego, 18/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT THE UNIVERSITY OF FLORIDA, 14/21 ABCD-USA Consortium: Research Project Site at CU Boulder, G95833762, G960602080
OpenAlex ID: W7221814696