ArticlemedRxiv : the preprint server for health sciences2025
Shared genetic architecture of brain age gap across 30 cohorts worldwide.
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106 authors.
Vilte BaltramonaityteDepartment of Psychology, University of Bath, Bath, United Kingdom.
Philippe JawinskiDepartment of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
Marlene StaginnusDepartment of Psychology, University of Bath, Bath, United Kingdom.
Mina ShahisavandiThe Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands.
Boglarka Z KovacsDepartment of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Isabel K SchuurmansThe Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands.
Constantinos ConstantinidesDepartment of Psychology, University of Bath, Bath, United Kingdom.
Ahmad R HaririDepartment of Psychology & Neuroscience, Duke University, Durham, United States.
Alexander TeumerDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Amanda L RodrigueDepartment of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, United States.
Ami TsuchidaGIN, IMN UMR 5293, CEA, CNRS, Université de Bordeaux, Bordeaux, France.
Amirhossein ManzouriCentre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm, Sweden.
Andriana KarukFIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
Anna E FürtjesLothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
Annalisa LellaClinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, United States.
Annchen R KnodtDepartment of Psychology & Neuroscience, Duke University, Durham, United States.
Antonia JülligDepartment of Experimental Psychology and Cognition Research, Justus-Liebig-University, Gießen, Germany.
Avshalom CaspiDepartment of Psychology & Neuroscience, Duke University, Durham, United States.
Benedicto Crespo-FacorroHospital Universitario Virgen del Rocio, IBIS-CSIC, CIBERSAM, Sevilla, Spain.
Brenda Wjh PenninxDepartment of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Catharina LavebrattMolecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Christine LochnerSAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, Tygerberg, South Africa.
Clarissa L YasudaDepartment of Neurology, State University of Campinas, Campinas, Brazil.
Dag AlnæsDepartment of Psychology, University of Oslo, Oslo, Norway.
Dan J SteinDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Daniel H MathalonDepartment of Psychiatry and Behavioral Sciences, University of California, San Francisco, California, United States.
David C GlahnDepartment of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, United States.
Dennis KloseDepartment of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Dylan J KiltschewskijSchool of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, Australia.
Edith Pomarol-ClotetFIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
Estela M BruxelBrazilian Institute of Neuroscience and Neurotechnology, Brazil.
Fabrice CrivelloGIN, IMN UMR 5293, CEA, CNRS, Université de Bordeaux, Bordeaux, France.
Fernando CendesDepartment of Neurology, State University of Campinas, Campinas, Brazil.
Gail DaviesLothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
Giovanni A SalumDepartment of Psychiatry and Legal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Hans J GrabeDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Heather J ZarDepartment of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.
Henning TiemeierHarvard T.H. Chan School of Public Health, Department of Behavioral and Social Sciences, Boston, United States.
Henry VölzkeUniversity Medicine Greifswald, Institute for Community Medicine, Greifswald, Germany.
Hervé LemaîtreGIN, IMN UMR 5293, CEA, CNRS, Université de Bordeaux, Bordeaux, France.
Iscia Lopes-CendesBrazilian Institute of Neuroscience and Neurotechnology, Brazil.
Ítalo Karmann AventuratoDepartment of Neurology, State University of Campinas, Campinas, Brazil.
Jean ShinCentre de recherche CHU Sainte-Justine and University of Montreal Montréal Canada.
Jessica A TurnerDepartment of Psychiatry and Behavioral Health, Wexner Medical Center, Ohio State University, Columbus, United States.
Joanna M WardlawInstitute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas of the Rio Grande Valley, Brownsville, TX, United States.
Jonathan C IpserDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Judith M FordDepartment of Psychiatry and Behavioral Sciences, University of California, San Francisco, California, United States.
Kang SimWest Region, Institute of Mental Health, Singapore, Singapore.
Karen SugdenDepartment of Psychology & Neuroscience, Duke University, Durham, United States.
Katharina WittfeldDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Kristina SalontajiDepartment of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Kristoffer Nt MånssonCentre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm, Sweden.
L Elliot HongDepartment of Psychiatry, The University of Texas Health Science Center, Houston, United States.
Lars T WestlyeDepartment of Psychology, University of Oslo, Oslo, Norway.
Lianne SchmaalCentre for Youth Mental Health, University of Melbourne, Melbourne, Australia.
Lucas T ItoDiscipline of Molecular Biology - Department of Biochemistry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Lucas Scárdua-SilvaDepartment of Neurology, State University of Campinas, Campinas, Brazil.
Marcos L SantoroDiscipline of Molecular Biology - Department of Biochemistry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
María Alemany-NavarroTranslational Psychiatry Group, Instituto de Biomedicina de Sevilla (IBiS)-CSIC, Seville, Spain.
Mark E BastinInstitute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom.
Mary S MuffordDivision of Human Genetics, University of the Witwatersrand, Johannesburg, South Africa.
Melissa J GreenSchool of Clinical Medicine, University of New South Wales, Sydney, Australia.
Murray J CairnsSchool of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, Australia.
Nadine ParkerCenter for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway.
Nathaniel W McGregorHuman and Systems Genetics Working Group, Department of Genetics, Stellenbosch University, Stellenbosch, South Africa.
Ole A AndreassenCenter for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway.
Oliver GruberSection for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
Oliver J WatkeysSchool of Clinical Medicine, Discipline of Psychiatry and Mental Health, University of New South Wales, Randwick, Australia.
Pedro M PanLaboratory of Integrative Neurosciences (LiNC), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Peter KochunovDepartment of Psychiatry, The University of Texas Health Science Center, Houston, United States.
Qian Hui ChewWest Region, Institute of Mental Health, Singapore, Singapore.
Rafael Romero-GarciaDepartment of Medical Physiology and Biophysics, Seville, Spain.
Raymond SalvadorFIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
Reremoana TheodoreDunedin Multidisciplinary Health and Development Research Unit, University of Otago, Dunedin, New Zealand.
Richie PoultonDunedin Multidisciplinary Health and Development Research Unit, University of Otago, Dunedin, New Zealand.
Robin BülowInstitute for Diagnostic Radiology and Neuroradiology, Greifswald, Germany.
Rodrigo A BressanLaboratory of Integrative Neurosciences (LiNC), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
Ryan L MuetzelDepartment of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Sebastian MarkettDepartment of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
Serena DefinaDepartment of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Sheri-Michelle KoopowitzDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Shir DahanClinical Neuroimaging Laboratory, Galway Neuroscience Center, College of Medicine, Nursing & Health Sciences, University of Galway, Galway, Ireland.
Simon R CoxLothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
Sintia BelangeroLaboratory of Integrative Neurosciences (LiNC), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
So M Vijayakumar KamalakannanClinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, United States.
Sophia I ThomopoulosImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, United States.
Stefan FrenzelDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Terrie E MoffittDepartment of Psychology & Neuroscience, Duke University, Durham, United States.
Theo Gm van ErpClinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, United States.
Tomas FurmarkDepartment of Psychology, Uppsala University, Uppsala, Sweden.
Tomas PausDepartments of Psychiatry and Neuroscience, University of Montreal, Montreal, Canada.
Uwe VölkerDepartment Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Vince D CalhounTri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State, Georgia Tech, Emory, Atlanta, United States.
Yann QuidéNeuroRecovery Research hub, School of Psychology, UNSW Sydney, Sydney, Australia.
Younghwa LeeSection for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
Yuri MilaneschiDepartment of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Zdenka PausovaCentre de recherche CHU Sainte-Justine and University of Montreal Montréal Canada.
Paul M ThompsonImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, United States.
Laura Km HanDepartment of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Jean-Baptiste PingaultDepartment of Clinical, Educational and Health Psychology London, University College London, United Kingdom.
James H ColeHawkes Institute, Department of Computer Science, University College London, London, United Kingdom.
Charlotte Am CecilDepartment of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Sarah E MedlandPsychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Danai DimaDepartment of Psychology and Neuroscience, City St George's, University of London, London, United Kingdom.
Esther WaltonDepartment of Psychology, University of Bath, Bath, United Kingdom.
Funding
FUNCTION BIRNU24RR021992 · NCRR · UNIVERSITY OF CALIFORNIA-IRVINE · PI POTKIN, STEVEN G · 2006 to 2010
$25.0MBIO-INFORMATICS RESEARCH NETWORK COORDINATING CENTER (BIRN-CC)U24RR025736 · NCRR · UNIVERSITY OF SOUTHERN CALIFORNIA · PI KESSELMAN, CARL · 2009 to 2011
$15.0MWorkforce Development CoreU54HG013247 · NHGRI · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · PI John Blangero · 2023 to 2026
$10.5MMining the Genomewide Scan: Genetic Profiles of Structural Loss in Schizophrenia: AD/ADRD supplementR01MH094524 · NIMH · THE MIND RESEARCH NETWORK · PI CALHOUN, VINCE D, TURNER, JESS · 2012 to 2021
$6.3MSOLAR-Eclipse Computational Tools for Imaging GeneticsR01EB015611 · NIBIB · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI KOCHUNOV, PETER V. · 2012 to 2024
$5.0MGenetics of Brain Structure and FunctionR01MH078111 · NIMH · TEXAS BIOMEDICAL RESEARCH INSTITUTE · PI BLANGERO, JOHN · 2006 to 2014
$4.5MGenetics of Brain Structure and FunctionR01MH078143 · NIMH · YALE UNIVERSITY · PI GLAHN, DAVID C · 2006 to 2014
$4.3MGenetics of Brain Structure and Function: Genome-Wide AssociationR01MH083824 · NIMH · YALE UNIVERSITY · PI GLAHN, DAVID C · 2008 to 2013
$3.3MNeuroimaging Dimensions at the Extremes of the Schizophrenia SpectrumR01MH134526 · NIMH · UNIVERSITY OF CALIFORNIA-IRVINE · PI Jess Turner, Theodorus G.M. van Erp · 2023 to 2026
$2.9MWomen focused Encounters for Resilience, Independence, Strength and Eudaimonia (WE RISE)R01MH134261 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Maile Ann Young Karris · 2023 to 2026
$2.8MLarge-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia OnsetRF1AG073593 · NIA · UNIVERSITY OF TEXAS AT AUSTIN · PI TUCKER-DROB, ELLIOT MAX · 2021 to 2021
$2.1MLarge-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia OnsetR01AG073593 · NIA · UNIVERSITY OF TEXAS AT AUSTIN · PI TUCKER-DROB, ELLIOT MAX · 2024 to 2025
$1.3MCSRD VA IK6 CX002519NCRR NIH HHS U24 RR021992NCRR NIH HHS U24 RR025736NHGRI NIH HHS U54 HG013247NIA NIH HHS R01 AG073593NIA NIH HHS RF1 AG073593NIBIB NIH HHS R01 EB015611NIH HHS S10 OD023696NIMH NIH HHS R01 MH078111NIMH NIH HHS R01 MH078143NIMH NIH HHS R01 MH083824NIMH NIH HHS R01 MH094524NIMH NIH HHS R01 MH134261NIMH NIH HHS R01 MH134526NIMH NIH HHS RF1 MH123163Wellcome Trust
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.
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