Shared genetic architecture of brain age gap across 30 cohorts worldwide

Deviations from normative brain ageing trajectories are linked to a wide range of adverse health outcomes. A number of brain age prediction models have been developed, based on various neuroimaging modalities, machine learning algorithms, training samples, and age ranges. However, it remains unknown whether these models converge on a shared genetic liability, and whether capturing this shared signal could provide a more sensitive marker of brain health than any single model alone. We first conducted a new brain age gap (BAG) GWAS in a sample of 60,735 individuals across 29 cohorts worldwide, and then applied genomic structural equation modelling to examine the shared genetic variance between five prior BAG GWASs and our new analysis, using a single latent BAG factor (30 cohorts overall). All six BAG GWASs loaded onto a single factor, explaining 63% of the total genetic variance. We identified 19 independent SNPs associated with the BAG factor, including four novel associations. Genetically, the BAG factor was positively correlated with multiple traits, with blood pressure, smoking, longevity, autism, and sleep showing putatively causal effects. A polygenic score (PGS) for the BAG factor showed associations with phenotypic BAGs already in childhood, with stronger links observed in adulthood. Phenome-wide association analyses indicated that BAG factor PGS captured associations with more health traits than individual BAG PGSs. Our findings underscore the importance of considering the shared variance across different BAG constructs to identify robust correlates of poor brain health.

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medRxiv
Published
2025-12-27
DOI
https://doi.org/10.64898/2025.12.23.25342890
Primary Topic
Genetic Associations and Epidemiology
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article
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article

Shared genetic architecture of brain age gap across 30 cohorts worldwide

Lucas Scardua-Silva, Fernando Cendes, María Alemany-Navarro, K. Sim et al.
medRxiv
Genetic Associations and Epidemiology
article

Shared genetic architecture of brain age gap across 30 cohorts worldwide

Lucas Scardua-Silva, Fernando Cendes, María Alemany-Navarro, K. Sim, Raymond Salvador, Kristoffer N. T. Månsson, Antonia Jüllig, Sophia I. Thomopoulos, Vilte Baltramonaityte, Daniel H. Mathalon, Esther Walton, Dag Alnæs, Annalisa Lella, Qian Hui Chew, Zdenka Pausová, Robin Bülow, Y. Milaneschi, Marcos Santoro, Benedicto Crespo‐Facorro, Mary Sophia Mufford, Siva Kamalakannan, Ami Tsuchida, C. Cecil, Andriana Karuk, Estela M. Bruxel, Constantinos Constantinides, H. Tiemeier, Reremoana F. Theodore, Ítalo Karmann Aventurato, Hervé Lemaître, Marlene Staginnus, Nathaniel W. McGregor, Anna E. Fürtjes, Síntia Belangero, Isabel K. Schuurmans, Catharina Lavebratt, Katharina Wittfeld, Clarissa Lin Yasuda, Nadine Parker, Dennis Klose, Karen Sugden, Ryan L. Muetzel, Melissa J. Green, Christine Löchner, Tomas Furmark, Boglárka Kovács, Dylan Kiltschewskij, Kristina Salontaji, Dan J. Stein, Avshalom Caspi, Brenda Wjh Penninx, Íscia Teresinha Lopes-Cendes, Alexander Teumer, Sebastian Markett, G Davies, Terrie E. Moffitt, T.G. van Erp, Fabrice Crivello, Jean-Baptiste Pingault, Hans J. Grabe, Ahmad R. Hariri, P. M. Pan, Prof Heather J Zar, Danai Dima, Oliver Watkeys, Stefan Frenzel, Rodrigo Bressan, V. D. Calhoun, Sarah E. Medland, Sheri-Michelle Koopowitz, Joanna M Wardlaw, Laura KM Han, Judith M Ford, Tomas Paus, Mina Shahisavandi, James H Cole, L. Elliot Hong, Shir Dahan, Lucas T Ito, Simon R Cox, Ole A Andreassen, Amirhossein Manzouri, Lianne Schmaal, Murray J Cairns, Yann Quide, Jean Shin, Edith Pomarol-Clotet, Annchen R Knodt, Oliver Gruber, John Blangero, Rafael Romero-Garcia, Philippe Jawinski, Richie Poulton, Amanda L Rodrigue, Younghwa Lee, Lars T Westlye, Peter Kochunov, Mark E Bastin, Jonathan C Ipser, Serena Defina, David C Glahn, Paul M Thompson, Jessica A. Turner, Uwe Völker, Henry Völzke
article en

Abstract

Deviations from normative brain ageing trajectories are linked to a wide range of adverse health outcomes. A number of brain age prediction models have been developed, based on various neuroimaging modalities, machine learning algorithms, training samples, and age ranges. However, it remains unknown whether these models converge on a shared genetic liability, and whether capturing this shared signal could provide a more sensitive marker of brain health than any single model alone. We first conducted a new brain age gap (BAG) GWAS in a sample of 60,735 individuals across 29 cohorts worldwide, and then applied genomic structural equation modelling to examine the shared genetic variance between five prior BAG GWASs and our new analysis, using a single latent BAG factor (30 cohorts overall). All six BAG GWASs loaded onto a single factor, explaining 63% of the total genetic variance. We identified 19 independent SNPs associated with the BAG factor, including four novel associations. Genetically, the BAG factor was positively correlated with multiple traits, with blood pressure, smoking, longevity, autism, and sleep showing putatively causal effects. A polygenic score (PGS) for the BAG factor showed associations with phenotypic BAGs already in childhood, with stronger links observed in adulthood. Phenome-wide association analyses indicated that BAG factor PGS captured associations with more health traits than individual BAG PGSs. Our findings underscore the importance of considering the shared variance across different BAG constructs to identify robust correlates of poor brain health.

medRxiv
South African Medical Research Council (ZA), University of Southern California (US), Uppsala University (SE), Oslo University Hospital (NO), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Universidade Federal do Rio Grande do Sul (BR), Department of Health and Social Care (GB), San Francisco VA Medical Center (US), NHS Lothian (GB), Harvard University (US), Université de Bordeaux (FR), University of Cape Town (ZA), Stockholm University (SE), The University of Queensland (AU), The University of Melbourne (AU), St George's, University of London (GB), Duke University (US), University of California, San Francisco (US), Universidade Estadual de Campinas (UNICAMP) (BR), King's College London (GB), University of Oslo (NO), Ollscoil na Gaillimhe – University of Galway (IE), University of the Witwatersrand (ZA), Hawassa University (ET), Justus-Liebig-Universität Gießen (DE), University of California, Irvine (US), QIMR Berghofer Medical Research Institute (AU), Heidelberg University (DE), Stellenbosch University (ZA), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Universitätsmedizin Greifswald (DE), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), The University of Texas Rio Grande Valley (US), Centre Hospitalier Universitaire Sainte-Justine (CA), The Ohio State University Wexner Medical Center (US), Karolinska Institutet (SE), Babeș-Bolyai University (RO), UNSW Sydney (AU), Humboldt-Universität zu Berlin (DE), Hunter Medical Research Institute (AU), Centro de Investigación Biomédica en Red de Salud Mental (ES), Orygen Youth Health (AU), Child Mind Institute (US), Amsterdam Neuroscience (NL), Fidmag Sisters Hospitallers (ES), UK Dementia Research Institute (GB), German Centre for Cardiovascular Research (DE), Instituto de Biomedicina de Sevilla (ES), Center for Translational Research in Neuroimaging and Data Science (US), Stockholm Health Care Services (SE), Institute of Mental Health (SG), Brazilian Institute of Neuroscience and Neurotechnology (BR), GGD Amsterdam (NL), Institute of Molecular Biology and Biophysics (RU), Boston Children's Museum (US), Amsterdam University Medical Centers (NL), Hospital Universitario Virgen del Rocío (ES), Red Cross War Memorial Children's Hospital (ZA), The University of Texas Health Science Center (US), University College London (GB), University of Bath (GB), Université de Montréal (CA), University of Newcastle Australia (AU), University of Otago (NZ), Neuroscience Research Australia (AU), Vrije Universiteit Amsterdam (NL), Universidade Federal de São Paulo (BR), Erasmus University Rotterdam (NL), The University of Texas Health Science Center at Houston (US), University of Edinburgh (GB)
Ministerio de Ciencia, Innovación y Universidades, National Institute for Health and Care Research, Department of Health and Social Care, Fundação de Amparo à Pesquisa do Estado de São Paulo, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Conselho Nacional de Desenvolvimento Científico e Tecnológico, NordForsk, Norges Forskningsråd, National Institutes of Health, NIHR Maudsley Biomedical Research Centre, Agencia Estatal de Investigación, National Institute of Mental Health, National Center for Research Resources
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