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

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

109 Scopus citations

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
DOIs	https://doi.org/10.1038/s41593-022-01042-4
State	Published - Apr 2022
Externally published	Yes

Funding

Funders	Funder number
Hersenstichting
Donders Centre for Cognitive Neuroimaging
Northern California Institute for Research and Education
Australian National Medical and Health Research Council
Alzheimer's Association
Stichting ALS Nederland
Age UK
Fresenius Medical Care North America
Alzheimer’s Research UK
Alzheimer's Society
Federal State of Mecklenburg-West Pomerania
Netherlands Twin Registry Repository
EU-AIMS
Young Investigator Grant
Initiative and Networking Fund
Helmholtz Association
BioClinica
U.S. Alzheimer’s Association
Fundación Familia Alonso
Leids Universitair Medisch Centrum
GGZ Noord Holland Noord
National Institutes of Health, Science Foundation Ireland
Erasmus Universiteit Rotterdam
University of Edinburgh
Heinz Nixdorf Stiftung
Stockholms Läns Landsting
MiND
K.G. Jebsen Foundation
Scottish Funding Council
King’s College London
Biobanking and Biomolecular Resources Research Infrastructure
Ministerio de Ciencia e Innovación
INPD
Erasmus Medical Center, Rotterdam
Erasmus University
Institut national de la santé et de la recherche médicale
Knut och Alice Wallenbergs Stiftelse
Haridus- ja Teadusministeerium
Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical Center
BMBF Neuron Eranet Synschiz
AbbVie
Biogen
Fundación Alicia Koplowitz
National Institute for Health and Care Research
National University of Ireland, Galway
Norges Forskningsråd
Erasmus Medisch Centrum
Netherlands Genomics Initiative
UK Dementia Research Institute
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Fédération pour la Recherche sur le Cerveau
BRIDGET
Mrs Gladys Row Fogo Charitable Trust
Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção
Radboud Universitair Medisch Centrum
Department of Psychology, University of Oslo
Ministerie van Volksgezondheid, Welzijn en Sport
Centro de Investigación Biomédica en Red de Salud Mental
South London and Maudsley NHS Foundation Trust
Fundación Mutua Madrileña
NWO Physical Sciences Division
BBMRI-NL
University of Queensland
Université Paris-Sud
Karolinska Institutet
KG Jebsen Stiftelsen
University Hospital Galway
Universiteit Utrecht
Lansdowne Foundation
Chiropractic and Osteopathic College of Australasia
PZ Sancta Maria Sint-Truiden
Dr. Einar Martens Fund
Universitetet i Bergen
Universiteit Leiden
CAPRI University of Antwerp
Maastricht Universitair Medisch Centrum
Alzheimer's Disease Neuroimaging Initiative
Universitair Centrum Sint-Jozef Kortenberg
University Medical Center Utrecht
RIDE2
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
Max Planck Institute for Psycholinguistics
Scottish Imaging Network
Araclon Biotech
European Research Council
DOD ADNI
Trond Mohn Research Foundation
European Community’s Horizon 2020 Programme
European Regional Development Fund
ANR-18-NEUR00002-01
Chief Scientist Office
Ministerie van Onderwijs, Cultuur en Wetenschap
Bristol-Myers Squibb Canada
Alzheimer's Drug Discovery Foundation
Ministry of Cultural Affairs
Horizon 2020
National Institute of Developmental Psychiatry for Children and Adolescents
Helse Vest
UK Research and Innovation
National Institute on Drug Abuse	U01DA051039, U01DA051016, U01DA051038, U01DA051018, U01DA051037, U01DA041106, U01DA041117, U01DA041028, U24DA041147, U01DA041148, U01DA041048, U24DA041123, U01DA041025, U01DA041134, U01DA041156, U01DA041089, U01DA041022, U01DA041120, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA041093
ANR-12-SAMA-0004	AAPG2019–GeBra
National Institute of Mental Health	R01MH085772, R21MH107327, R01MH116147, R01MH117601, RC2MH089995, R01MH118349, R01MH120125, K99MH116115
National Institutes of Health	LBC1936
Not added	51.02.062, 51.02.061, 433-09-229, 056-13-015
National Health and Medical Research Council	350833, GNT1008080, R01MH116147, 1037196, 1090148, U01AG068057, 1095127, 401184, 401162, 1176716, P41EB015922, R01AG02238.NJ, 568940, GNT1090148, ZEN-20-644609, 1063960, 1066177, 1103623
Commonwealth Scientific and Industrial Research Organisation	PI17/01056, PI14/00639, PI14/00918
ZonMW TOP	FOR2107, 912110210
NWO-NIHC	NWO-MagW 480-04-004, 433-09-220, NWO/SPI 56-464-14192
Horizon 2020 Framework Programme	772376
Brain and Behavior Research Foundation	25034
Not added	16/ERCD/3797
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg	NO246/10-2, JA 1890/7-2, KI 588/14-2, KI 588/14-1, NO 246/10-1, JA 1890/7-1, KR 3822/7-1, KR 3822/7-2, Dan3/012/17
Conselho Nacional de Desenvolvimento Científico e Tecnológico	573974/2008-0
Vici Innovation Program	016-130-669
ZonMw	10-000-1002
European Union-funded FP6	LSHM-CT- 2007-037286
Bundesministerium für Bildung und Forschung	01EV0711, 91211021, 01ZX1314A, NE 1383/14-1, SFB 940, TRR 265, 01EW1810, 01GS08152, SM 80/7-2, 223273, AERIAL 01EE1406A, 01EE1406B, RI908/11-2
European Commission	249795
Federeal Ministry of Science	2011/50740-5
Rijksuniversiteit Groningen	60-60600-97-193, 1750102007010, 433-09-242, R01MH62873
Comisión Nacional de Investigación Científica y Tecnológica	21180871
Max-Planck-Gesellschaft	APP1172917, APP1103623, FOR2107 Wi3439/3-2, APP1158127
Sophia Children’s Hospital Foundation	S18-68
University of Southern California	H2020/2014–2020
University Hospitals	HA7070/4, MzH 3/020/20, HA7070/2-2, HA7070/3
University of Sydney	APP1095127, R01MH118349, Ne2254/1-2, R01MH120125, R21MH107327-01
Dutch Health Research Council	10-000-1001
National Healthcare Group, Singapore	SIG/05004, SIG/05028, SIG /1103
Shanghai Pujiang Project	18PJ1400900
National Institute on Aging	U01AG024904, R01AG060470, R01AG022381, P01AG055367, R56AG058854, R01AG064955, U01AG068057, R01AG059874, R01AG054002, R01AG050595
Medical Research Foundation and Medical Research Council	5U54EB020403-05, MR/R00465X/1, 1R56AG058854-01, MR/S020306/1
Medical Research Council	G0701120, G1001245, MR/R024065/1, MR/N000390/1, MR/M013111/1
Australian Research Council	1405325
Instituto de Salud Carlos III	CP18/00003, SAM16PE07CP1, PI16/02012, PI19/024
Instituto de Investigación Marqués de Valdecilla	NCT0235832, NCT02534363
Row Fogo Centre for Research into Ageing	AD.ROW4.35, FID3668413
Fondation de France	00081242
Seventh Framework Programme	FP7- HEALTH-2013-2.2.1-2-603196
Throne-Holst Foundation	R01 AG054002, R01AG060470
Fundação de Amparo à Pesquisa do Estado de São Paulo	2014/50917-0, 2008/57896-8
Research Institute for Diseases in the Elderly	014-93-015
Netherlands Organization of Scientific Research NWO	175.010.2005.011, 911-03-012
Innovative Medicines Initiative	AIMS-2-TRIALS
Netherlands Consortium for Healthy Aging	050-060-810
Fondation pour la Recherche Médicale	DPA20140629802
Fondation de l'Avenir pour la Recherche Médicale Appliquée	AP-RM-17-013
European Union Marie Curie Research Training Network	MRTN-CT-2006-035987
Singapore Bioimaging Consortium	RP C009/2006, SFB 940/2, R01MH117601, R01AG059874
H2020 CoMorMent	K99MH116115
Dutch National Science Agenda NeurolabNL	2016/13737-0, IDEX-2012, 2016/04983-7, 400‐17‐602, FOR2107 RI 908/11-1, collaborative-project-2010
ERANID	PR-ST-0416-10004
Testosterone and Mental Health	RO1 MH085772-01A1
Seventh Framework Programme	115916, 695313, 785907, 602805, 667302, 777394, 643051, 728018, 802998, 230374, 602450, 115300, 603196, 278948, 847776, 603016
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	156791
U.S. Department of Defense	W81XWH-12-2-0012
National Institute of Biomedical Imaging and Bioengineering	P41EB015922, U54EB020403
Siemens Healthineers	11559, 568969, 917.46.370, 908.02.123, 109308
Madrid Regional Government	B2017/BMD-3740 AGES-CM-2
Key Project of Shanghai Science and Technology Innovation Plan	16JC1420402
Fondation Leducq	APP1173025, 16 CVD 05
Vetenskapsrådet	521-2011-4622, 2006-2992, 2006-986, 2003-5485, 521-2014-3487, 2008-2167, K2012-61X-15078-09-3, 2017-00949
National Alliance for Research on Schizophrenia and Depression	20244
EU Joint Programme Neurodegenerative Disorders	916.19.151
National Institute on Alcohol Abuse and Alcoholism	R01 AA026881
Royal Society	221890/Z/20/Z
Neuroscience Campus Amsterdam	1RC2 MH089995, 184.033.111, 184.021.007
National Natural Science Foundation of China	81930095, 91630314, 81801773
Agence Nationale de la Recherche	ANR-12-SAMA-0004
Helse Sør-Øst RHF	2019101, 2019107
South African Medical Research Council	276082
Health Research Board	HRA_POR/2011/100
Science and Technology Commission of Shanghai Municipality	2018SHZDZX01
National Children’s Foundation Tallaght	JR19/00024, R01 AG022381, R56AG058854, R01AG058854, R01 AG050595, R01R56 AG037985, P01 AG055367
Rotterdam Study	01ZZ0403, 01ZZ0103, 01ZZ9603
National Health & Medical Research Council of Australia	APP1008080
Deutsche Forschungsgemeinschaft	DA1151/5-2, SFB-TRR58, FOR2107 DA1151/5-1
Eranet Neuron	AF12-NEUR0008-01–WM2NA
EU Joint Programme – Neurodegenerative Disease Research	MR/N027558/1
NWO-Groot	480-15-001/674
Avera Institute for Human Genetics	R01-HD074051
Wellcome Trust	221890
Sophia Foundation	S18-20

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10.1038/s41593-022-01042-4

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@article{fe10f1d88b124f0b9bd38799c2a8cae6,

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.",

author = "{the IMAGEN Consortium} and 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 Harris, {Mathew A.} and Hartman, {Catharina A.} and Heany, {Sarah J.} and Walter Heindel and Heslenfeld, {Dirk J.} and Sarah Hohmann and Stein, {Dan J.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = apr,

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

language = "אנגלית",

volume = "25",

pages = "421--432",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Research",

number = "4",

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TY - JOUR

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

AU - the IMAGEN Consortium

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 - Harris, Mathew A.

AU - Hartman, Catharina A.

AU - Heany, Sarah J.

AU - Heindel, Walter

AU - Heslenfeld, Dirk J.

AU - Hohmann, Sarah

AU - Stein, Dan J.

PY - 2022/4

Y1 - 2022/4

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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.

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JF - Nature Neuroscience

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ER -

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

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