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

Research output: Contribution to journalArticlepeer-review

Rachel M Brouwer, Marieke Klein, Katrina L Grasby, Hugo G Schnack, Neda Jahanshad, Jalmar Teeuw, Sophia I Thomopoulos, Emma Sprooten, Carol E Franz, Nitin Gogtay, William S Kremen, Matthew S Panizzon, Loes M Olde Loohuis, Christopher D Whelan, Moji Aghajani, Clara Alloza, Dag Alnæs, Eric Artiges, Rosa Ayesa-Arriola, Gareth J Barker & 30 more Mark E Bastin, Elisabet Blok, Erlend Bøen, Isabella A Breukelaar, Joanna K Bright, Elizabeth E L Buimer, Robin Bülow, Dara M Cannon, Simone Ciufolini, Nicolas A Crossley, Christienne G Damatac, Paola Dazzan, Casper L de Mol, Sonja M C de Zwarte, Sylvane Desrivières, Covadonga M Díaz-Caneja, Nhat Trung Doan, Katharina Dohm, Juliane H Fröhner, Janik Goltermann, Antoine Grigis, Dominik Grotegerd, Laura K M Han, Mathew A Harris, Tianye Jia, Tiago Reis Marques, Marta Di Forti, Evangelos Vassos, Celso Arango, Robin M Murray

Original languageEnglish
Pages (from-to)421-432
Number of pages12
JournalNature Neuroscience
Issue number4
Early online date5 Apr 2022
Accepted/In press28 Feb 2022
E-pub ahead of print5 Apr 2022
PublishedApr 2022

Bibliographical note

Funding Information: 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. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

King's Authors


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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