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Genetic variants associated with longitudinal changes in brain structure across the lifespan

Abstract

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

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Fig. 1: Phenotypic brain changes throughout the lifespan.
Fig. 2: Annual rates of change Δ per cohort for each structure.
Fig. 3: Genetic effects on rates of brain changes throughout the lifespan.
Fig. 4: Summary of findings for two top SNPs.
Fig. 5: Genetic overlap with other phenotypes.

Data availability

This work is a meta-analysis. Upon publication, the meta-analytic results will be made available from the ENIGMA consortium webpage (http://enigma.ini.usc.edu/research/download-enigma-gwas-results). Cohort-level data can be shared upon reasonable request, after permission of cohort principal investigators. Individual-level data can be shared with interested investigators, subject to local and national ethics regulations and legal requirements that respect the informed consent forms and national laws of the country of origin of the persons scanned. Figures that contain cohort-level (meta) data are as follows: Figs. 1 and 2, Extended Data Figs. 1, and 2 and Supplementary Figs 1, 3, 8 and 10.

Public data used in this work include the ABCD cohort (data release 3.0, accessible through https://nda.nih.gov/abcd; https://doi.org/10.15154/1519007), the ADNI cohort (accessible through adni.loni.usc.edu) and the UK Biobank cohort (data request 11559, https://www.ukbiobank.ac.uk).

Code availability

The code for processing of individual cohorts (including imaging and quality control, imputation and GWAS protocol) can be found on http://enigma.ini.usc.edu/ongoing/enigma-plasticity-working-group/. Code for the meta-regression is available through GitHub (https://github.com/RMBrouwer/GWAS_meta_regression).

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Acknowledgements

Data used in preparing this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, many investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators may be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. A full list of consortium authors can be found in the Supplementary Information. Funding: The ENIGMA-Plasticity Working Group is part of the ENIGMA World Aging Center, funded by NIA grants R56 AG058854 and R01 AG058854. The ENIGMA Consortium core funding was supported by NIH Consortium Grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence. 1000BRAINS: 1000BRAINS is a population-based cohort based on the Heinz-Nixdorf Recall Study and is supported, in part, by the German National Cohort. We thank the Heinz Nixdorf Foundation (Germany) for their generous support in terms of the Heinz Nixdorf Study. The authors are supported by the Initiative and Networking Fund of the Helmholtz Association (Svenja Caspers) and the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 785907 (Human Brain Project SGA2; Svenja Caspers, Sven Cichon and Katrin Amunts). This work was further supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Program (grant 01ZX1314A; Sven Cichon) and by the Swiss National Science Foundation (SNSF, grant 156791; Sven Cichon). ABCD: Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multi-site, longitudinal study designed to recruit more than 10,000 children aged 9–10 years and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123 and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The ABCD data repository grows and changes over time. The ABCD data used in this report came from Data Release 3.0 (https://doi.org/10.15154/1519007). ADNI: Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol Myers Squibb; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ALS Utrecht: The authors acknowledge grants supporting their work from the European Union’s Horizon 2020 Research and Innovation Programme (H2020/2014–2020) under grant agreements 667302 (CoCA), 728018 (Eat2beNICE), 785907 (HBP SGA2) and 772376 (EScORIAL) and the Netherlands ALS Foundation. BDC: Brain Dynamics Centre (BDC), Sydney—cohort is funded by a National Health & Medical Research Council of Australia Project Grant (APP1008080). BHRCS: The Brazilian High Risk Cohort Study (BHRCS) was supported by the National Institute of Developmental Psychiatry for Children and Adolescents (INPD) Grant: Fapesp 2014/50917-0 CNPq 465550/2014-2. BIG: This study used the BIG database, which was established in Nijmegen in 2007. This resource is now part of Cognomics, a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical Center and the Max Planck Institute for Psycholinguistics. The Cognomics Initiative is supported by the participating departments and centers and by external grants, including grants from the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL) and the Hersenstichting Nederland. In particular, the authors would also like to acknowledge grants supporting their work from the Netherlands Organization for Scientific Research (NWO)—that is, the NWO Brain & Cognition Excellence Program (grant 433-09-229) and the Vici Innovation Program (grant 016-130-669 to B.F.). Additional support is received from the European Community’s Seventh Framework Programme (FP7/2007—2013) under grant agreements n° 602805 (Aggressotype), n° 603016 (MATRICS), n° 602450 (IMAGEMEND) and n° 278948 (TACTICS) and from the European Community’s Horizon 2020 Programme (H2020/2014—2020) under grant agreements n° 643051 (MiND) and n° 667302 (CoCA). BrainSCALE: The BrainSCALE study is a collaborative project between Netherlands Twin Register (NTR) at the Vrije Universiteit (VU) Amsterdam and University Medical Center Utrecht (UMCU). The BrainSCALE study was funded by Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 51.02.061 to H.E.H., NWO 51.02.062 to D.B., NWO-NIHC Programs of Excellence 433-09-220 to H.E.H., NWO-MagW 480-04-004 to D.B. and NWO/SPI 56-464-14192 to D.B.); FP7 Ideas: the European Research Council (ERC-230374 to D.B.), Universiteit Utrecht (High Potential Grant to H.E.H.), Netherlands Twin Registry Repository (NWO-Groot 480-15-001/674 to D.B.) and Neuroscience Campus Amsterdam (NCA). Biomolecular Resources Research Infrastructure (BBMRI–NL, 184.021.007 and 184.033.111) developmental trajectories of psychopathology (NIMH 1RC2 MH089995); and the Avera Institute for Human Genetics. Cape Town: The CTAAC study was supported by grant R01-HD074051. DBSOS: The DBSOS study is partially funded by the Brain and Behavior Foundation (NARSAD) by an Independent Investigator grant (20244). The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMW). The neuroimaging infrastructure is supported by ZonMW TOP (912110210), the NWO Physical Sciences Division and the SURFsara supercomputing center (Cartesius Compute Cluster). FOR2107: This work is part of the German multicenter consortium ‘Neurobiology of affective disorders. A translational perspective on brain structure and function’, funded by the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); Forschungsgruppe/Research Unit FOR2107). Grant agreements included the following: FOR2107 DA1151/5-1 and DA1151/5-2 to U.D.; SFB-TRR58, Projects C09 and Z02 to U.D.; the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of Münster (grant Dan3/012/17 to U.D.); KR 3822/7-1 and KR 3822/7-2 to A.K.; KI 588/14-1 and KI 588/14-2; and NO 246/10-1 and NO 246/10-2 to M.M.N. A.J. was in particular involved as principal investigator in WP6, multi-method data analytics (JA 1890/7-1 and JA 1890/7-2). The FOR2107 study was also supported by the German Federal Ministry of Education and Research (BMBF), through ERA-NET NEURON, ‘SynSchiz: linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation’ (01EW1810 to M.R.) and the German Research Foundation (DFG grant FOR2107; RI908/11-2 to M.R.). Generation R: Netherlands Organization for Health Research and Development (ZonMw) TOP project 91211021. Sophia Children’s Hospital Foundation (Stichting Vrienden van het Sophia) project S18-68. The Generation R sample further reports the following support: Supercomputing resources for imaging processing were supported by the NWO Physical Sciences Division (Exacte Wetenschappen) and SURFsara (Cartesius compute cluster, https://www.surf.nl); neuroimaging data analysis was supported, in part, by Sophia Foundation Project S18-20 and Erasmus University Fellowship awarded to R.L.M. HGUGM: This work was supported by Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012 and PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds; European Union Seventh Framework Program under grant agreements FP7- HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN) and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 115916, Project PRISM and grant agreement 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. HUBIN: The HUBIN study was funded by the Swedish Research Council (2003-5485, 2006-2992, 2006-986, 2008-2167, K2012-61X-15078-09-3, 521-2011-4622, 521-2014-3487 and 2017-00949); regional agreement on medical training and clinical research between the Stockholm County Council and the Karolinska Institutet; and the Knut and Alice Wallenberg Foundation. IMAGEN: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the interplay between cultural, biological and subjective factors in drug use pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907), the FP7 project MATRICS (603016), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministerium für Bildung und Forschung (BMBF grants 01GS08152 and 01EV0711 and Forschungsnetz AERIAL 01EE1406A and 01EE1406B), Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-2, SFB 940, TRR 265 and NE 1383/14-1), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1) and the National Institutes of Health (NIH)-funded ENIGMA (grants 5U54EB020403-05 and 1R56AG058854-01). Further support was provided by grants from the ANR (ANR-12-SAMA-0004, AAPG2019–GeBra), the Eranet Neuron (AF12-NEUR0008-01–WM2NA and ANR-18-NEUR00002-01–ADORe), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1) and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. LBC1936: We thank the Lothian Birth Cohort 1936 members who took part in this study and Lothian Birth Cohort 1936 research team members and radiographers who collected, entered and checked data used in this paper. MRI acquisition and analyses were conducted at the Brain Research Imaging Centre, Neuroimaging Sciences, University of Edinburgh (www.bric.ed.ac.uk), which is part of the SINAPSE (Scottish Imaging Network—A Platform for Scientific Excellence) collaboration (www.sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. The LBC1936 and this research are supported by Age UK (Disconnected Mind project), the UK Medical Research Council (MRC; G0701120, G1001245, MR/M013111/1 and MR/R024065/1) and the University of Edinburgh. NCNG: The NCNG sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr. Einar Martens Fund, the K.G. Jebsen Foundation and the Research Council of Norway, to S.L.H., V.M.S. and T.E. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant 10-000-1002) and financial contributions by participating universities and mental healthcare organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe and Rob Giel Onderzoekscentrum). NeuroIMAGE: The NeuroIMAGE study was supported by NIH grant R01MH62873 (to S.V.F.), NWO Large Investment Grant 1750102007010 (to J.B.), ZonMW grant 60-60600-97-193, NWO grants 056-13-015 and 433-09-242 and matching grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare and Vrije Universiteit Amsterdam. The research leading to these results also received support from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 278948 (TACTICS), 602805 (Aggressotype), 603016 (MATRICS) and 602450 (Imagemend) and the Innovation Medicine Initiative grants 115300 (EU-AIMS) and 777394 (AIMS-2-TRIALS). NUIG: We would like to thank the radiologists at the University Hospital Galway and the participants who generously gave their time to make this study possible. The NUIG sample was supported and funded by the National University of Ireland Galway (NUIG) Millennium Fund and the Health Research Board (HRA_POR/2011/100). OATS: We gratefully acknowledge and thank the OATS participants, their supporters and the research team. The Older Australian Twin Study (OATS) is supported by Australian NHMRC/Australian Research Council Strategic Award (grant 401162) and NHMRC project grant 1405325. This study was facilitated through Twins Research Australia, a national resource in part supported by a Centre for Research Excellence from the NHMRC. DNA was extracted by Genetic Repositories Australia (NHMRC grant 401184). Genome-wide genotyping at the Diamantina Institute, University of Queensland, was partly funded by a CSIRO Flagship Collaboration Fund Grant. PAFIP: PAFIP was supported by the Instituto de Salud Carlos III (PI14/00639, PI14/00918 and PI17/01056) and Fundación Instituto de Investigación Marqués de Valdecilla (NCT0235832 and NCT02534363). No pharmaceutical company has financially supported the study. Rotterdam Study: The GWAS datasets are supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011 and 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) and the Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. We thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera, M. Peters and C. Medina-Gomez for their help in creating the GWAS database and K. Estrada, Y. Aulchenko and C. Medina-Gomez for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. SHIP: The SHIP study is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. Sydney MAS: We gratefully acknowledge and thank the Sydney MAS participants, their supporters and the research team. The Sydney Memory and Ageing Study (MAS) is supported by National Health & Medical Research Council of Australia program grants (350833, 568969 and 109308) and a Capacity Building Grant (568940). DNA samples were extracted by Genetic Repositories Australia, an Enabling Facility, which is supported by National Health & Medical Research Council of Australia grant 401184. UK Biobank: This research has been conducted using the UK Biobank Resource under application 11559. UMCU: The UMCU cohort contains a.o. UTWINS and GROUP. UTWINS was funded by the Netherlands Organization for Health Research and Development (ZonMw) (908.02.123 and 917.46.370 to H.E.H.) and by the European Union Marie Curie Research Training Network (MRTN-CT-2006-035987). The GROUP study is partially funded through the Geestkracht programme of the Dutch Health Research Council (Zon-Mw, grant 10-000-1001) and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly and Janssen Cilag) and universities and mental healthcare organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Center and GGZ Noord Holland Noord. Groningen: University Medical Center Groningen and the mental health institutions Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical center The Hague. Maastricht: Maastricht University Medical Center and the mental health institutions GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt and OPZ Rekem. Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). UNSW: The UNSW study was supported by the Australian National Medical and Health Research Council (NHMRC) Program Grant 1037196, Project Grant 1066177 and the Lansdowne Foundation. We gratefully acknowledge the Janette Mary O’Neil Research Fellowship to J.M.F. Personal funding: A.L.W.B. received funding from the National Children’s Foundation Tallaght, Ireland. R.M.B. was supported by NIA R56AG058854 and R01AG058854 to the ENIGMA World Aging Center. C.D.-C. was supported by Instituto de Salud Carlos III, Juan Rodés Grant (JR19/00024). C.E.F. was supported by R01 AG050595, R01 AG022381, P01 AG055367 and R01R56 AG037985. D.A.l. was supported by the South-Eastern Norway Regional Health Authority (2019107). D.J.S. is supported by the SAMRC. D.v.d.M. was supported by Research Council of Norway grant 276082. E.G.J. was supported by the Swedish Research Council (2003-5485, 2006-2992, 2006-986, 2008-2167, K2012-61X-15078-09-3, 521-2011-4622, 521-2014-3487 and 2017-00949); regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet; the Knut and Alice Wallenberg Foundation; and the HUBIN project. E.S.P. is supported by Hypatia Tenure Track Grant (Radboudumc); NARSAD Young Investigator Grant (Brain and Behavior Research Foundation ID: 25034); and the Christine Mohrmann Fellowship. E.V. was supported by National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. F.N. was supported by German Research Foundation NE 1383/14-1. H.B. was supported by NHMRC Australia. G.A.S. was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil; grant 573974/2008-0), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Brazil; grant 2008/57896-8) and the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil). H.E.H. was supported by NIA R56AG058854 and R01AG058854 to the ENIGMA World Aging Center. H.J.G. has received research funding from the EU Joint Programme Neurodegenerative Disorders (JPND). H.H.H.A. was supported by the Netherlands Organization for Health Research and Development (ZonMW, grant 916.19.151). I.A.B. was supported by University of Sydney Post-graduate Award. I.N. was supported by DFG Ne2254/1-2. J.B.J.K. was supported by NHMRC Dementia Research Team Grant APP1095127. J.H. was supported by R21MH107327-01. J.L.S. was supported by grants R01MH118349 and R01MH120125. J.W. was supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, the Alzheimer’s Society and Alzheimer’s Research UK (J.W.), the Row Fogo Charitable Trust through the Row Fogo Centre for Research into Ageing and the Brain (AD.ROW4.35 and BRO-D.FID3668413) and the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (16 CVD 05). K.L.G. was supported by grant APP1173025. K.S. was supported by research grants from the National Healthcare Group, Singapore (SIG/05004, SIG/05028 and SIG /1103) and the Singapore Bioimaging Consortium (RP C009/2006). L.D. was supported by R01AG059874 and R01MH117601. J.H.F. was supported by SFB 940/2 and the German Ministry of Education and Research (BMBF grants 01EV0711 and 01EE1406B). L.H.v.d.B. was supported by the Netherlands ALS Foundation. O.A.A. was supported by the Research Council of Norway (223273), KG Jebsen Stiftelsen and H2020 CoMorMent (847776). L.M.O.L. was supported by K99MH116115. L.P. received funding from the German Research Foundation (DFG), the Ministry of Science and Education (BMBF) and European Union. L.T.W. is funded by the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (ERC Starting Grant 802998), the Research Council of Norway (249795), the South-East Norway Regional Health Authority (2019101) and the Department of Psychology, University of Oslo. M.K. was supported by funding from the Dutch National Science Agenda NeurolabNL project (grant 400‐17‐602). M.L.P.M. was supported by the French funding agency ANR (ANR-12-SAMA-0004), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris-Descartes-University (collaborative-project-2010) and Paris-Sud-University (IDEX-2012). M.L.S. was supported by FAPESP: 2016/13737-0 and 2016/04983-7. M.M.N. was supported by the German Research Foundation (DFG grants FOR2107 and NO246/10-2). M.N.S. was supported by the Deutsche Forschungsgemeinschaft (DFG grants TRR 265, SFB 940 and SM 80/7-2) and the German Ministry of Education and Research (BMBF grants 01EV0711 and 01EE1406B). M.R. was supported by DFG FOR2107 RI 908/11-1 and RI 908/11-2 and BMBF Neuron Eranet Synschiz 01EW1810. M.S.K. was supported by the National Health and Medical Research Council, Australia Project Grant (GNT1008080) and Career Development Fellowship (GNT1090148). M.S.P. was supported by NIA R01AG02238.NJ. L.D. was supported by R01AG059874 and R01MH117601. P.M.T. and S.I.T. were supported by NIH R01AG058854 to the ENIGMA World Aging Center, U01AG068057, R01MH116147, P41EB015922, and a Zenith Grant (ZEN-20-644609) from the U.S. Alzheimer’s Association. P.R.S. was supported by National Health and Medical Research Council, Australia grants 1037196, 1063960 and 1176716. R.A.-A. is funded by a Miguel Servet contract from the Carlos III Health Institute (CP18/00003), carried out on Fundación Instituto de Investigación Marqués de Valdecilla. P.G.F. received funding from the German Research Foundation, the European Union and the Federeal Ministry of Science. R.A.B. was supported by the European Research Council. S.I.B. was supported by FAPESP 2016/04983-7, FAPESP 2011/50740-5 and INCT (CNPq/FAPESP) 2014/50917-0. S.E.F. was supported by the Max Planck Society. S.E.M. was supported by NHMRC APP1103623, APP1172917 and APP1158127. S.H.W. was supported by DFG FOR2107 Wi3439/3-2 and BMBF Neuron ERANET Synschiz 01EW1810. S.L.H. was supported by the University of Bergen, the Trond Mohn Research Foundation and Helse Vest. S.R.C. was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 221890/Z/20/Z). T.E.l. was funded by the Research Council of Norway, the South-Eastern Norway Regional Health Authority, Oslo University Hospital and a research grant from Mrs. Throne-Holst. T.H. was supported by grants from the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of Münster (grant MzH 3/020/20) and the German Research Foundation (DFG grants HA7070/2-2, HA7070/3 and HA7070/4). T.J. was supported by the National Natural Science Foundation of China (81801773, 81930095 and 91630314), the Shanghai Pujiang Project (18PJ1400900), the Key Project of Shanghai Science and Technology Innovation Plan (16JC1420402), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01) and the Zhangjiang lab. T.R.M. was supported by the Medical Research Council (UK). T.W. was supported by the Netherlands Organization for Health Research and Development (ZonMw) TOP project (91211021) and Sophia Children’s Hospital Foundation (Stichting Vrienden van het Sophia) project S18-68. V.M. was supported by CONICYT fellowships 21180871. U.F.M. was supported by the Throne-Holst Foundation. V.M.S. was supported by the Research Council of Norway (grant 223273 NORMENT). W.S.K. was supported by NIA grants R01 AG050595, R01 AG022381, R01AG060470 and R01 AG054002 and NIAAA grant R01 AA026881.

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Conceptualization: B.F., C.E.F., H.E.H., M.S.P., N.J., P.M.T., R.M.B., S.E.M. and W.S.K. Central analysis and coordination: B.F., C.D.W., E. Sprooten, H.E.H., H.G.S., M.K., K.L.G., N.J., P.M.T., R.M.B., S.E.M. and S.I.T. Core writing team: B.F., H.E.H., K.L.G., M.K., N.J., P.M.T., R.M.B. and S.E.M. Visualization: J. Teeuw, M.K. and R.M.B. Cohort principle investigators: A.H., A.J., A.K., A.L.W.B., A.P.J., B.C.F., B.T.B., B.W.J.H.P., C. Arango, C.M., D. Ames, D.I.B., E.G.J., F.N., G.A.S., G. Schumann, H.B., H.E.H., H.F., H.G., H.H.H.A., H.J.G., H.L., H.W., I.A., I.N., J.-L.M., J.H., J.H.V., J.K. Buitelaar, J.M.F., J.O., J. Trollor, K.A., K.S., L.H.v.d.B., L.P., L.T.W., M.A.I., M.H.J., M.J.W., M.N.S., M.S.K., O.A.A., P.A.G., P.B.M., P.G.F., P.J.H., P.M.P., P.R.S., P.S., P.S.S., R.A.B., R.A.O., R.L.M., R.M.M., R.S.K., R.W., S. Caspers, S. Cichon, S.E.F., S.I.B., S.R.C., T.B., T.E.l., T. Espeseth, T.H., T. Kircher, T.W., U.D., U.F.M. and W.C. Imaging data collection: A.G., A.L.W.B., A.P.J., A.Z., A.v.d.L., B.I., B.M., C.A.M., C.A.H, C.D.-C., C.J., C.M., D. Ames, D.G., D.I.B., D.J.H., D.M.C., D.T.-G., E.A., E. Bøen, E.G.J., E. Shumskaya, F.N., F. Stein, G.J.B., G.R., G. Sudre, H.-J.W., H.F., H.H.H.A., I.A., I.A.B., J.-L.M., J.G., J.H., J.H.F., J. Janssen, J.M.F., J.M.W., J.R., J. Trollop, K.A., K.D., K.S., L.H.v.d.B., L.T.W., M.A.I., M.E.B., M.G.J.C.K., M.J.W., M.L.P.M., M.N.S., M.S.K., N.E.M.v.H., N.O., N.S., O.A.A., P.A.G., P.D., P.M.P., P.R.J., P.S., R.A.-A., R.B., R.K.L., R.R., S. Desrivières, S.H., S.M., T.R.M., T.W., T.W.M., U.D., V.O.G., W.H. and W.W. Genetic data collection: A.J.F., A.L.W.B., B.M., B.T.B., B.W.J.H.P., C. Arango, C.D.-C., C.M., D.I.B., D.W.M., E.A., E.G.J., F.N., F. Stein, F. Streit, G.H., G. Sudre, H.F., H.H.H.A., I.A.B., J.-L.M., J.B.J.K., J.G.-P., J.H., J.J.H., J.M.F., J.R., J. Trollop, J.V.-B., K.A.M., K.S., L.H.v.d.B., M.D.F., M.J.W., M.L.P.M., M.L.S., M.M.N., M.N.S., M.R., M.S.K., N.S., O.A.A., P.D., P.M.P., P.R.S., P.S., R.A.O., R.R., S. Cichon, S. Desrivières, S.E.F., S.H.W., S.I.B., S.L.H., S.M., T.R.M., T.W.M., U.D. and V.M.S. Imaging data analysis: A.G., A.H.Z., A.P.J., A. Thalamuthu, A.Z., B.J.O., B.M., C. Alloza, C.G.D., C.J., C.L.d.M., D. Alnæs, D.G., D.K., D.M.C., D.T.-G., E. Blok, E.E.L.B., E. Shumskaya, E. Sprooten, F.N., G.B., G. Sudre, G.V.R., H.-J.W., H.J.G., I.A., I.A.B., J. Jiang, J.K. Bright, J.M.W., K.S., K.W., L.K.M.H., L.N., L.T.W., M.A., M.A.H., M.G.J.C.K., M.S.K., N.A.C., N.E.M.v.H., N.J., N.S., N.T., R.B., R.C.W.M., R.M.B., R.R., S. Ciufolini, S.I.T., S.J.H., S.M.C.d.Z., S.R.C., S.T., T.J., T. Karali, T.W., U.D., V.M., W.H. and W.W. Genetic data analysis: A.J.F., A. Teumer, A. Thalamuthu, B.M., B.T.B., C.G.D., C.L.d.M., D.v.E., D.v.d.M., E. Blok, E. Sprooten, E.V., F. Streit, G.B., G. Davies, G. Donohoe, G. Sudre, G.V.R., J.B., J.B.J.K., J.G.-P., J.L.S., J.M.F., J.P.O.F.T.G., J. Teeuw, K.R., K.S., L.D., L.M.O.L., M.A.I., M.J.K., M.L.S., M.R., N.J., N.J.A., P.R.J., R.M.B., R.M.T., S. Dalvie, S.E.M., S.H.W., S.I.B., S.L.H., S.M.C.d.Z., S.P., T.J. and Y.M.

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Correspondence to Rachel M. Brouwer or Hilleke E. Hulshoff Pol.

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B.F. has received speaking fees from MEDICE Arzneimittel Pütter GmbH & Co. B.W.J.H.P. has received research funding from Jansen Research and Boehringer Ingelheim. C.A. has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. C.D.W. is an employee of Biogen, Inc. D.J.S. has received research grants and/or consultancy honoraria from Lundbeck and Sun. G.J.B. receives honoraria for teaching from GE Healthcare. H.B. is on the Advisory Board Nutricia Australia. H.E.H. has received travel fees for membership of the Steering Committee of the Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research and for two presentations from Philips. These concerned activities were unrelated to the submitted work. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. L.P. has served as an advisor or consultant to Shire, Takeda and Roche. L.P. has also received speaking fees from Shire and Infectopharm. The present work is unrelated to these relationships. M.H.J. received grant support from the Brain and Behavior Foundation (NARSAD) Independent Investigator grant 20244. M.M.N. has received fees for memberships in Scientific Advisory Boards from the Lundbeck Foundation and Robert Bosch Stiftung and for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt. M.M.N. was reimbursed travel expenses for a conference participation by Shire Deutschland GmbH. M.M.N. receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities are outside the submitted work. N.J. and P.M.T. are multiple principal investigators of a research grant from Biogen, Inc for work unrelated to the contents of this manuscript. O.A.A. has received speaker’s honoraria from Lundbeck and has been a consultant for HealthLytix. P.S.S. reports on/off payment for an advisory board meeting of Biogen. T.B. served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire and Infectopharm. T.B. also received conference support or speaker’s fees from Lilly, Medice and Shire and received royalties from Hogrefe, Kohlhammer, CIP Medien and Oxford University Press. The present work is unrelated to these relationships. T.E.l. has received speaker’s fees from Lundbeck. T.R.M. has received honoraria for speaking and chairing engagements from Lundbeck, Janssen and Astellas. Other authors declare no conflicts of interest.

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Extended data

Extended Data Fig. 1 Demographics and analysis.

Overview of demographics (left). Per cohort, an age distribution is displayed, based on mean and standard deviation of the age at baseline. Cohorts of European ancestry are displayed in green, non-European cohorts are displayed in yellow. On the right, the total number of included subjects is displayed and a pie-chart of the distribution of diagnostic groups (pink) and subjects not belonging to diagnostic groups - often healthy subjects (aqua). Overview of analysis pipeline (right).

Extended Data Fig. 2 Correlations between change rates.

Pearson correlations between rates of change and between baseline intracranial volume and rates of change in the largest adolescent cohort (top, N = 1068) and the largest cohort in older age (bottom, N = 624) in phase 1. The size of the correlations is displayed by color and size of the circles.

Supplementary information

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Reporting Summary

Supplementary Tables 1–19

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Brouwer, R.M., Klein, M., Grasby, K.L. et al. Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nat Neurosci 25, 421–432 (2022). https://doi.org/10.1038/s41593-022-01042-4

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