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

The IMAGEN Consortium

doi:10.1038/s41593-022-01042-4

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

The IMAGEN Consortium

UMC University Medical Center Utrecht
VU Amsterdam
University of California at San Diego
Donders Institute for Brain, Cognition and Behaviour
QIMR Berghofer Medical Research Institute
Utrecht Institute of Linguistics OTS
Keck School of Medicine of USC
American Psychiatric Association
Oklahoma City Veterans Affairs Medical Center
UCLA Semel Institute for Neuroscience and Human Behavior
Biogen Inc.
Instituut Lorentz for Theoretical Physics
Complutense University of Madrid
University of Oslo
Université Paris-Saclay
Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain.
University of Zaragoza; Instituto de Investigacion Sanitaria de Aragon (IIS) and Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Zaragoza, Spain.
University of Cantabria
University of Edinburgh
University of Sydney
National University of Ireland Galway
King's College London
Pontificia Universidad Catolica de Chile
Erasmus University Medical Center
Institut für Kernphysik
TU Dresden
Centre for Population Neuroscience and Precision Medicine
Fudan University
University of Auckland
Brain Research New Zealand - Rangahau Roro Aotearoa
SLaM South London and Maudsley NHS Foundation Trust
University Medical Center Göttingen
National Institute of Mental Health (NIH)

Research output: Contribution to journal › Article › peer-review

137 Citations (Scopus)

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.

Original language	English
Pages (from-to)	421-432
Number of pages	12
Journal	Nature Neuroscience
Volume	25
Issue number	4
Early online date	5 Apr 2022
DOIs	https://doi.org/10.1038/s41593-022-01042-4 https://doi.org/10.1038/s41593-022-01042-4
Publication status	Published - 5 Apr 2022

Keywords

Aging/genetics
Brain
Genome-Wide Association Study
Humans
Longevity/genetics
Magnetic Resonance Imaging

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@article{9ee2594d83fd4311964adb48c0ff84d8,

title = "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.",

keywords = "Aging/genetics, Brain, Genome-Wide Association Study, Humans, Longevity/genetics, Magnetic Resonance Imaging",

author = "Brouwer, \{Rachel M.\} and Marieke Klein and Grasby, \{Katrina L.\} and Schnack, \{Hugo G.\} and Neda Jahanshad and Jalmar Teeuw and Thomopoulos, \{Sophia I.\} and Emma Sprooten and Franz, \{Carol E.\} and Nitin Gogtay and Kremen, \{William S.\} and Panizzon, \{Matthew S.\} and \{Olde Loohuis\}, \{Loes M.\} and Whelan, \{Christopher D.\} and Moji Aghajani and Clara Alloza and Dag Aln{\ae}s and Eric Artiges and Rosa Ayesa-Arriola and Barker, \{Gareth J.\} and Bastin, \{Mark E.\} and Elisabet Blok and Erlend B{\o}en and Breukelaar, \{Isabella A.\} and Bright, \{Joanna K.\} and Buimer, \{Elizabeth E.L.\} and Robin B{\"u}low and Cannon, \{Dara M.\} and Simone Ciufolini and Crossley, \{Nicolas A.\} and Damatac, \{Christienne G.\} and Paola Dazzan and \{de Mol\}, \{Casper L.\} and \{de Zwarte\}, \{Sonja M.C.\} and Sylvane Desrivi{\`e}res and D{\'i}az-Caneja, \{Covadonga M.\} and Doan, \{Nhat Trung\} and Katharina Dohm and Fr{\"o}hner, \{Juliane H.\} and Janik Goltermann and Antoine Grigis and Dominik Grotegerd and Han, \{Laura K.M.\} and Tianye Jia and Morgan, \{Catherine A.\} and Gustavo Sudre and Evangelos Vassos and Celso Arango and Luise Poustka and Philip Shaw and \{The IMAGEN Consortium\}",

note = "Funding Information: B.F. has received speaking fees from MEDICE Arzneimittel P{\"u}tter 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{\textquoteright}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 {\"A}rzteblatt. 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{\textquoteright}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{\textquoteright}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{\textquoteright}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: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = apr,

day = "5",

doi = "10.1038/s41593-022-01042-4",

language = "English",

volume = "25",

pages = "421--432",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - Genetic variants associated with longitudinal changes in brain structure across the lifespan

AU - Brouwer, Rachel M.

AU - Klein, Marieke

AU - Grasby, Katrina L.

AU - Schnack, Hugo G.

AU - Jahanshad, Neda

AU - Teeuw, Jalmar

AU - Thomopoulos, Sophia I.

AU - Sprooten, Emma

AU - Franz, Carol E.

AU - Gogtay, Nitin

AU - Kremen, William S.

AU - Panizzon, Matthew S.

AU - Olde Loohuis, Loes M.

AU - Whelan, Christopher D.

AU - Aghajani, Moji

AU - Alloza, Clara

AU - Alnæs, Dag

AU - Artiges, Eric

AU - Ayesa-Arriola, Rosa

AU - Barker, Gareth J.

AU - Bastin, Mark E.

AU - Blok, Elisabet

AU - Bøen, Erlend

AU - Breukelaar, Isabella A.

AU - Bright, Joanna K.

AU - Buimer, Elizabeth E.L.

AU - Bülow, Robin

AU - Cannon, Dara M.

AU - Ciufolini, Simone

AU - Crossley, Nicolas A.

AU - Damatac, Christienne G.

AU - Dazzan, Paola

AU - de Mol, Casper L.

AU - de Zwarte, Sonja M.C.

AU - Desrivières, Sylvane

AU - Díaz-Caneja, Covadonga M.

AU - Doan, Nhat Trung

AU - Dohm, Katharina

AU - Fröhner, Juliane H.

AU - Goltermann, Janik

AU - Grigis, Antoine

AU - Grotegerd, Dominik

AU - Han, Laura K.M.

AU - Jia, Tianye

AU - Morgan, Catherine A.

AU - Sudre, Gustavo

AU - Vassos, Evangelos

AU - Arango, Celso

AU - Poustka, Luise

AU - Shaw, Philip

AU - The IMAGEN Consortium

N1 - 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.

PY - 2022/4/5

Y1 - 2022/4/5

N2 - 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.

AB - 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.

KW - Aging/genetics

KW - Brain

KW - Genome-Wide Association Study

KW - Humans

KW - Longevity/genetics

KW - Magnetic Resonance Imaging

UR - https://www.scopus.com/pages/publications/85127652829

U2 - 10.1038/s41593-022-01042-4

DO - 10.1038/s41593-022-01042-4

M3 - Article

C2 - 35383335

SN - 1097-6256

VL - 25

SP - 421

EP - 432

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 4

ER -

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

Abstract

Keywords

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