Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Dennis van der Meer; Abdel Abdellaoui; Dorret I Boomsma; Eco J C de Geus; Anouk den Braber; Jouke-Jan Hottenga; Dennis van 't Ent; Ole A Andreassen; Writing Committee for the ENIGMA-CNV Working Group

doi:10.1001/jamapsychiatry.2019.3779

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Dennis van der Meer, Abdel Abdellaoui, Dorret I Boomsma, Eco J C de Geus, Anouk den Braber, Jouke-Jan Hottenga, Dennis van 't Ent, Ole A Andreassen, Writing Committee for the ENIGMA-CNV Working Group

Research output: Contribution to Journal › Article › Academic › peer-review

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Abstract

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

Original language	English
Pages (from-to)	420-430
Number of pages	11
Journal	JAMA Psychiatry
Volume	77
Issue number	4
Early online date	30 Oct 2019
DOIs	https://doi.org/10.1001/jamapsychiatry.2019.3779
Publication status	Published - Apr 2020

Funding

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), the FP7 projects IMAGEMEND(602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants, SM 80/7-2, SFB 940/2), the Medical Research Foundation and Medical research council (grant MR/R00465X/1). Further support was provided by grants from: ANR (project AF12-NEUR0008-01 – WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Fondation pour la Recherche Médicale (DPA20140629802), the Fondation de l’Avenir, Paris Sud University IDEX 2012; 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. Funding/Support: This study is supported in part advisory board member for Nutricia Australia and has received research funding from the European Union Joint Programme Neurodegenerative Disorders and the National Health and Medical Research Council of Australia. Dr Brouwer has received grants from the Netherlands Organization for Scientific Research (MagW and Brain and Cognition) and Utrecht University. Dr Caspers has received grants from the Initiative and Networking Fund of the Helmholtz Association and the European Union Horizon 2020 Research and Innovation Program under Grant Agreement 785907. Dr Ching has received research support from Biogen. Dr Crespo-Facorro has received personal fees from Janssen-Cilag, Otsuka Pharmaceutical, and Lundbeck. Dr Desrivieres has received grants from the Medical Research Council, Medical Research Foundation, NIHR Biomedical Research Centre, and National Institutes of Health. Dr Di Forti has received personal fees from Janssen Pharmaceutica. Dr Doherty has received grants from the Wellcome Trust. Dr Fladby has received grants from the Norwegian Research Council and the European Union Joint Programme Neurodegenerative Disorders. Dr Fukunaga has received grants from the Japan Society for the Promotion of Science and Japan Agency for Medical Research and Development. Dr Grabe has received grants from the German Research Foundation (DFG), German Ministry of Education and Research (BMBF), the DAMP Foundation, the European Union Joint Programme Neurodegenerative Disorders, and the European Social Fund as well as grants and personal fees from Fresenius Medical Care; personal fees from Neuraxpharm and Janssen-Cilag. Dr Haavik has received grants from Stiftelsen Kristian Gerhard Jebsen and personal fees from Eli Lilly and Co, Shire, and Biocodex. ECHO-DEFINE: The ECHO study acknowledges funding from a Medical Research Council (MRC) Centre Grant to Owen (G0801418), the Wellcome Trust (Institutional Strategic Support Fund (ISSF) to van den Bree and Clinical Research Training Fellowship to Doherty), the Waterloo Foundation (WF 918-1234 to van den Bree), the Baily Thomas Charitable Fund (2315/1 to van den Bree), National Institute of Mental Health (NIMH 5UO1MH101724 to van den Bree and Owen), the IMAGINE-ID study (funded by MRC (MR/N022572/1 to van den Bree and Owen)). The DEFINE study was supported by a Wellcome Trust Strategic Award (100202/Z/12/Z) to Owen. QTIM: The QTIM study was supported by the National Institute of Child Health and Human Development (R01 HD050735), and the National Health and Medical Research Council (NHMRC 486682, 1009064), Australia. Genotyping was supported by NHMRC (389875). Medland is supported in part by an NHRC fellowship (APP1103623). deCODE genetics: deCODE genetics acknowledges support from the Innovative Medicines Initiative Joint Undertaking under grant agreements’ no. 115008 (NEWMEDS) and no. 115300 (EUAIMS) of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007-2013), EU- PAFIP: The PAFIP study was supported by Instituto de Salud Carlos III, FIS 00/3095, 01/3129, PI020499, PI060507, PI10/00183, the SENY Fundació Research Grant CI 2005-0308007, and the Fundación Marqués de Valdecilla API07/011. Biological samples from our cohort were stored at the Valdecilla Biobank and genotyping services were conducted at the Spanish “Centro Nacional de Genotipado” (CEGEN-ISCIII). Dr Hehir-Kwa has received grants from the Netherlands Organization for Scientific Research. Dr Hillegers has received grants from the National Alliance for Research on Schizophrenia and Depression Brain and Behavior Foundation and Netherlands Organisation for Health Research and Development. Dr Jacquemont has received grants from Brain Canada, Canada Research Chair, and Canadian Institutes of Health Research. Dr Jahanshad has received grants from the National Institutes of Health and Biogen. Dr Linden has received grants from the Wellcome Trust and book royalties from the Oxford University Press and Palgrave Macmillan. Dr Liu has received grants from the National Institutes of Health. Dr Astri Lundervold has received personal fees from Shire. Dr Mather has received grants from the National Health and Medical Research Council of Australia and Australian Research Council. Dr Moberget has received grants from the Southern and Eastern Norway Regional Health Authority. Dr Owen has received grants from the Medical Research Council, Wellcome Trust, and Takeda Pharmaceuticals. Dr Reis Marques has received personal fees from Lundbeck, Janssen Pharmaceutica, Astellas Pharma, and Angelini. Dr Rucker has received grants from the Wellcome Trust and NIHR Biomedical Research Centre. Dr Sachdev has received grants from the National Health and Medical Research Council of Australia, Australian Research Council, National Institute of Aging, Holden Foundation, Wicking Trust, Vincent Fairfax Family Foundation, and Yulgilbar Foundation as well as personal fees from Biogen. Dr Schofield has received grants from the National Health and Medical Research Council of Australia paid to Neuroscience Research Australia. Dr Steen has received grants from the Research Council of Norway. Dr Stein has received personal fees from Lundbeck and Sun Pharmaceutical Industries. Dr Thalamuthu has received grants from the National Health and Medical Research Council of Australia. Dr van den Bree has received grants from Takeda Pharmaceuticals. Dr Dale is a founder of, holds equity in, and serves on the scientific advisory board of CorTechs Lab; is a member of the scientific advisory board of Human Longevity; has received grants from GE Healthcare; and is a member of the Alzheimer’s Disease Genetics Consortium (ADGC), Enhancing Imaging Genetics through Meta-Analysis (ENIGMA), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), and Psychiatric Genomics Consortium (PGC) groups. Dr Westlye has received grants from the Research Council of Norway, Southern and Eastern Norway Regional Health Authority, and European Research Council. Dr Thompson has received grants from Biogen. Dr Andreassen has received grants from the Research Council of Norway, Stiftelsen Kristian Gerhard Jebsen, Southern and Eastern Norway Regional Health Authority, and National Institutes of Health; personal fees from Lundbeck; and serves as a consultant for HealthLytix. No other disclosures were reported. OATS: The Older Australian Twins Study (OATS) is funded by NHMRC Program Grant ID1045325 and the NHMRC/Australian Research Council Strategic Award (ID401162). Twins Research Australia was supported by the NHRMC Enabling Grant 310667. We also thank the OATS participants and Research Team. Betula: The Betula study was funded by the Knut and Alice Wallenberg (KAW) foundation. The Freesurfer segmentations on the Betula sample was performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at HPC2N in Umeå, Sweden. MCIC/COBRE is funded by the National Institutes of Health studies R01EB006841, P20GM103472, and P30GM122734. NTR: The NTR cohort was supported by the Netherlands Organization for Scientific Research (NWO), MW904-61-193 (de Geus & Boomsma), MaGW-nr: 400-07-080 (van ‘t Ent), MagW 480-04-004 (Boomsma), NWO/SPI 56-464-14192 (Boomsma), the European Research Council, ERC-230374 (Boomsma), and Amsterdam Neuroscience. Funding for genotyping was obtained from the National Institutes of Health (NIMH U24 MH068457-06; Grand Opportunity grants 1RC2 MH089951, and 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. StrokeMRI: StrokeMRI was supported by the Norwegian ExtraFoundation for Health and Rehabilitation (2015/FO5146), the Research Council of Norway (249795, 262372), the South-Eastern Norway Regional Health Authority (2014097, 2015044, 2015073), and the Department of Psychology, University of Oslo. EPIGEN-Dublin: The EPIGEN-Dublin cohort was supported by a Science Foundation Ireland Research Frontiers Programme award (08/RFP/GEN1538). FP7 funded grant no. 602450 (IMAGEMEND) and EU funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC). GOBS: The GOBS study data collection was supported in part by the National Institutes of Health (NIH) grants: R01 MH078143, R01 MH078111 and R01 MH083824 with work conducted in part in facilities constructed under the support of NIH grant C06 RR020547. NCNG: 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, the Research Council of Norway, to le Hellard, Steen and Espeseth. The Bergen group was supported by grants from the Western Norway Regional Health Authority (Grant 911593 to AL, Grant 911397 and 911687 to AJL). by grants U54 EB20403, R01MH116147, and R56AG058854 from the National Institutes of Health, grant 609020 from the European Union Seventh Framework Programme, and grants 223273 and 276082 from the Research Council Norway. Part of this work was performed using the Service for Sensitive Data (TSD), which is developed and operated by the TSD Service Group and owned by the University of Oslo. Additional funding details can be found in eAppendix 2 in Supplement 1. Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (www.cognomics.nl), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud university medical centre and the Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative has received supported from the participating departments and centres and from external grants, i.e. the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL), the Hersenstichting Nederland, and the Netherlands Organisation for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant ‘Language in Interaction’, the European Community’s Seventh Framework Programme (FP7/2007– 2013) under grant agreements n° 602450 (IMAGEMEND), n°278948 (TACTICS), and n°602805 (Aggressotype) as well as from the European Community’s Horizon 2020 programme under grant agreement n° 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. EPIGEN-UK (Sisodiya): The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to the Wolfson Trust and the Epilepsy Society for supporting the Epilepsy Society MRI scanner. SHIP: SHIP 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 no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide SNP typing in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. HUNT: The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Movement Sciences, NTNU – Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. HUBIN: The HUBIN study was financed by the Swedish Research Council (K2010-62X-15078-07-2, K2012-61X-15078-09-3, K2015-62X-15077-12-3, 2017-00949), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet. Osaka: Osaka study was supported by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS: Grant Number JP18dm0207006), Brain/MINDS & beyond studies (Grant Number JP19dm0307002) and Health and Labor Sciences Research Grants for Comprehensive Research on Persons with Disabilities (Grant Number H26-seishin-ippan-012) from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (KAKENHI; Grant Number JP25293250 and JP16H05375). Some computations were performed at the Research Center for Computational Science, Okazaki, Japan. 1000BRAINS: The 1000BRAINS study was funded by the Institute of Neuroscience and Medicine, Research Center Juelich, Germany. We thank the Heinz Nixdorf Foundation (Germany) for the generous support of the Heinz Nixdorf Recall Study on which 1000BRAINS is based. We also thank the scientists and the study staff of the Heinz Nixdorf Recall Study and 1000BRAINS. Funding was also granted by the Initiative and Networking Fund of the Helmholtz Association (Caspers) and the European Union’s Horizon 2020 Research and Innovation Program under Grant Agreement 785907 (Human Brain Project SGA2; Amunts, Caspers, Cichon). SYS: The SYS Study is supported by Canadian Institutes of Health Research. Brainscale: The Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Boomsma), 51.02.060 (Hilleke Hulshoff Pol), 668.772 (Boomsma & Hulshoff Pol); NWO/SPI 56-464-14192 (Boomsma), the European Research Council (ERC-230374) (Boomsma), High Potential Grant Utrecht University (Hulshoff Pol), NWO Brain and Cognition 433-09-220 (Hulshoff Pol). ENIGMA: ENIGMA is supported in part by NIH grants U54 EB20403, R01MH116147, and R56AG058854. PING: Data collection and sharing for the Pediatric Imaging, Neurocognition and Genetics (PING) Study (National Institutes of Health Grant RC2DA029475) were funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. A full list of PING investigators is at http://pingstudy.ucsd.edu/investigators.html.

Funders	Funder number
ANR-12-SAMA-0004
Avera Institute for Human Genetics
BBMRI-NL
BRIDGET
Canada Research Chair
Department of Psychology, University of Oslo
Dr Einar Martens Fund
Dutch Health Research Council	10-000-1001
ENIGMA Consortium
ERANID	PR-ST-0416-10004
EU-AIMS	115300-2
EU-FP7
Erasmus Medical Centre
European Union Horizon 2020 Research and Innovation Program
European Union Joint Programme Neurodegenerative Disorders
European Union-funded FP6	LSHM-CT-2007-037286
European Union’s Horizon 2020 research and innovation program	785907
FP7 projects IMAGEMEND	603016
FP7-PEOPLE-2013-COFUND
FP7/2007	602805, 278948
Federal State of Mecklenburg-West Pomerania
Fondation de l’Avenir
GGZ Noord Holland Noord
German Ministry of Education and Research
High Potential Grant Utrecht University
Holden Foundation
ISSF
Institute of Neuroscience and Medicine, Research Center Juelich
K.G. Jebsen Foundation
Medical Research Foundation and Medical research council	MR/R00465X/1
Mind	ERC-2010-AdG 268800-NEUROSCHEMA
NHMRC/Australian Research Council	ID401162
NHRMC	310667
NIH Consortium	U54 EB020403
National Health and Medical Research Council of Australia
National Institutes of Health and Biogen
National Institutes of Health, Science Foundation Ireland	16/ERCD/3797
National and Health Medical Research Council	ID568969, ID350833, ID109308
Netherlands Organization for Scientific Research	51.02.060, MW904-61-193, MagW 480-04-004, 668.772, 400-07-080, NWO/SPI 56-464-14192
Norwegian ExtraFoundation for Health and Rehabilitation	2015/FO5146
Paris Sud University
Stiftelsen Kristian Gerhard Jebsen, Southern and Eastern Norway Regional Health Authority
Testosterone and Mental Health	RO1 MH085772-01A1
UK Department of Health’s NIHR Biomedical Research Centres
Wicking Trust
National Institutes of Health	R01 MH078111, R01 MH083824, RC2DA029475, 609020, C06 RR020547, P30GM122734, R01 MH078143, R01EB006841, P20GM103472
National Institute of Mental Health	1RC2 MH089951, 1RC2 MH089995, R01MH116147, 5UO1MH101724, MR/N022572/1, U24 MH068457-06, 100202/Z/12/Z
National Institute on Drug Abuse
National Institute on Aging	R56AG058854
National Institute of Child Health and Human Development	R01 HD050735
Biogen
Shire
Norges Teknisk-Naturvitenskapelige Universitet
King’s College London
South London and Maudsley NHS Foundation Trust
Fondation Brain Canada
Japan Agency for Medical Research and Development	JP25293250, JP16H05375
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Alliance for Research on Schizophrenia and Depression	20244
Wellcome Trust
Horizon 2020 Framework Programme	643051
Waterloo Foundation	WF 918-1234
EU Joint Programme – Neurodegenerative Disease Research	MR/N027558/1
NIHR Bristol Biomedical Research Centre
Cilag
Takeda Pharmaceuticals International
Canadian Institutes of Health Research
Medical Research Council	G0801418, MR/N000390/1
National Institute for Health Research
European Commission	286213
European Research Council	ERC-230374
Australian Research Council
National Health and Medical Research Council	486682, 389875, ID1045325, 1009064
Baily Thomas Charitable Fund
Science Foundation Ireland	08/RFP/GEN1538
Deutsche Forschungsgemeinschaft	SM 80/7-2, SFB 940/2
Agence Nationale de la Recherche	AF12-NEUR0008-01 – WM2NA
ZonMw	908-02-123
Universiteit Utrecht
Svenska Forskningsrådet Formas
Bundesministerium für Bildung und Forschung	01GS08152, 01ZZ0403, 01EV0711, AERIAL 01EE1406A, 01EE1406B, 01ZZ0103, 01ZZ9603
Fondation pour la Recherche Médicale
Eidgenössischen Departement für Wirtschaft, Bildung und Forschung
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	NWO-VIDI 917-46-370, 9120818
National Human Rights Commission	APP1103623
Karolinska Institutet
Knut och Alice Wallenbergs Stiftelse
Stockholms Läns Landsting
Vetenskapsrådet	K2015-62X-15077-12-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3, 2017-00949
Fondation de France
Instituto de Salud Carlos III	01/3129, PI060507, CI 2005-0308007, FIS 00/3095, PI020499, PI10/00183
Helse Midt-Norge
Cultural Affairs and Missions Sector, Ministry of Higher Education
European Social Fund
Seventh Framework Programme	223273, 602450, 276082
Helse Vest Regionalt Helseføretak	911687, 911397, 911593
Universitetet i Bergen
Norges forskningsråd	262372, 249795
Helse Sør-Øst RHF	2015073, 2015044, 2014097
Horizon 2020	695313
Hersenstichting
Medical Research Foundation
Helmholtz Association
Innovative Medicines Initiative	115300, 115008
Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives	DPA20140629802
Norges Idrettshøgskole	U54 EB20403
Damp Stiftung
Yulgilbar Foundation
Vincent Fairfax Family Foundation
Fundación Marqués de Valdecilla	API07/011

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Netherlands Twin Register (NTR)

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10.1001/jamapsychiatry.2019.3779

jamapsychiatry_van_der_meer_2019_oi_190082_Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and CognitionFinal published version, 942 KBLicence: Article 25fa Dutch Copyright Act

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van der Meer, D., Abdellaoui, A., Boomsma, D. I., de Geus, E. J. C., den Braber, A., Hottenga, J.-J., van 't Ent, D., Andreassen, O. A., & Writing Committee for the ENIGMA-CNV Working Group (2020). Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition. JAMA Psychiatry, 77(4), 420-430. https://doi.org/10.1001/jamapsychiatry.2019.3779

@article{a4f7a66b269745349e7ad2e3b11b45f1,

title = "Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition",

abstract = "Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.",

author = "{van der Meer}, Dennis and S{\o}nderby, {Ida E} and Tobias Kaufmann and Walters, {G Bragi} and Abdel Abdellaoui and David Ames and Katrin Amunts and Micael Andersson and Armstrong, {Nicola J} and Manon Bernard and Blackburn, {Nicholas B} and John Blangero and Boomsma, {Dorret I} and Henry Brodaty and Brouwer, {Rachel M} and Robin B{\"u}low and Wiepke Cahn and Calhoun, {Vince D} and Svenja Caspers and Cavalleri, {Gianpiero L} and Ching, {Christopher R K} and Sven Cichon and Simone Ciufolini and Aiden Corvin and Benedicto Crespo-Facorro and Curran, {Joanne E} and Shareefa Dalvie and Paola Dazzan and {de Geus}, {Eco J C} and {de Zubicaray}, {Greig I} and {de Zwarte}, {Sonja M C} and Norman Delanty and {den Braber}, Anouk and Sylvane Desrivieres and {Di Forti}, Marta and Doherty, {Joanne L} and Gary Donohoe and Stefan Ehrlich and Else Eising and Thomas Espeseth and Fisher, {Simon E} and Tormod Fladby and Oleksandr Frei and Vincent Frouin and Masaki Fukunaga and Thomas Gareau and Glahn, {David C} and Grabe, {Hans J} and Groenewold, {Nynke A} and {\'O}mar G{\'u}stafsson and Jan Haavik and Haberg, {Asta K} and Ryota Hashimoto and Hehir-Kwa, {Jayne Y} and Hibar, {Derrek P} and Hillegers, {Manon H J} and Per Hoffmann and Laurena Holleran and Jouke-Jan Hottenga and {Hulshoff Pol}, {Hilleke E} and Masashi Ikeda and S{\'e}bastien Jacquemont and Neda Jahanshad and Christiane Jockwitz and Stefan Johansson and J{\"o}nsson, {Erik G} and Masataka Kikuchi and Knowles, {Emma E M} and Kwok, {John B} and {Le Hellard}, Stephanie and Linden, {David E J} and Jingyu Liu and Arvid Lundervold and Lundervold, {Astri J} and Martin, {Nicholas G} and Mather, {Karen A} and Mathias, {Samuel R} and McMahon, {Katie L} and McRae, {Allan F} and Medland, {Sarah E} and Torgeir Moberget and Clara Moreau and Morris, {Derek W} and M{\"u}hleisen, {Thomas W} and Murray, {Robin M} and Nordvik, {Jan E} and Lars Nyberg and {Olde Loohuis}, {Loes M} and Ophoff, {Roel A} and Owen, {Michael J} and Tomas Paus and Zdenka Pausova and Peralta, {Juan M} and Bruce Pike and Carlos Prieto and Quinlan, {Erin Burke} and Reinbold, {C{\'e}line S} and {Reis Marques}, Tiago and Rucker, {James J H} and Sachdev, {Perminder S} and Sando, {Sigrid B} and Schofield, {Peter R} and Schork, {Andrew J} and Gunter Schumann and Jean Shin and Elena Shumskaya and Silva, {Ana I} and Sisodiya, {Sanjay M} and Steen, {Vidar M} and Stein, {Dan J} and Strike, {Lachlan T} and Tamnes, {Christian K} and Alexander Teumer and Anbupalam Thalamuthu and Diana Tordesillas-Guti{\'e}rrez and Anne Uhlmann and {\'U}lfarsson, {Magn{\'u}s {\"O}} and {van 't Ent}, Dennis and {van den Bree}, {Marianne B M} and Evangelos Vassos and Wei Wen and Katharina Wittfeld and Wright, {Margaret J} and Tetyana Zayats and Dale, {Anders M} and Srdjan Djurovic and Ingrid Agartz and Westlye, {Lars T} and Hreinn Stef{\'a}nsson and K{\'a}ri Stef{\'a}nsson and Thompson, {Paul M} and Andreassen, {Ole A} and {Writing Committee for the ENIGMA-CNV Working Group}",

year = "2020",

month = apr,

doi = "10.1001/jamapsychiatry.2019.3779",

language = "English",

volume = "77",

pages = "420--430",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "4",

}

van der Meer, D, Abdellaoui, A, Boomsma, DI , de Geus, EJC , den Braber, A , Hottenga, J-J , van 't Ent, D, Andreassen, OA & Writing Committee for the ENIGMA-CNV Working Group 2020, 'Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition', JAMA Psychiatry, vol. 77, no. 4, pp. 420-430. https://doi.org/10.1001/jamapsychiatry.2019.3779

TY - JOUR

T1 - Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

AU - van der Meer, Dennis

AU - Sønderby, Ida E

AU - Kaufmann, Tobias

AU - Walters, G Bragi

AU - Abdellaoui, Abdel

AU - Ames, David

AU - Amunts, Katrin

AU - Andersson, Micael

AU - Armstrong, Nicola J

AU - Bernard, Manon

AU - Blackburn, Nicholas B

AU - Blangero, John

AU - Boomsma, Dorret I

AU - Brodaty, Henry

AU - Brouwer, Rachel M

AU - Bülow, Robin

AU - Cahn, Wiepke

AU - Calhoun, Vince D

AU - Caspers, Svenja

AU - Cavalleri, Gianpiero L

AU - Ching, Christopher R K

AU - Cichon, Sven

AU - Ciufolini, Simone

AU - Corvin, Aiden

AU - Crespo-Facorro, Benedicto

AU - Curran, Joanne E

AU - Dalvie, Shareefa

AU - Dazzan, Paola

AU - de Geus, Eco J C

AU - de Zubicaray, Greig I

AU - de Zwarte, Sonja M C

AU - Delanty, Norman

AU - den Braber, Anouk

AU - Desrivieres, Sylvane

AU - Di Forti, Marta

AU - Doherty, Joanne L

AU - Donohoe, Gary

AU - Ehrlich, Stefan

AU - Eising, Else

AU - Espeseth, Thomas

AU - Fisher, Simon E

AU - Fladby, Tormod

AU - Frei, Oleksandr

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Gareau, Thomas

AU - Glahn, David C

AU - Grabe, Hans J

AU - Groenewold, Nynke A

AU - Gústafsson, Ómar

AU - Haavik, Jan

AU - Haberg, Asta K

AU - Hashimoto, Ryota

AU - Hehir-Kwa, Jayne Y

AU - Hibar, Derrek P

AU - Hillegers, Manon H J

AU - Hoffmann, Per

AU - Holleran, Laurena

AU - Hottenga, Jouke-Jan

AU - Hulshoff Pol, Hilleke E

AU - Ikeda, Masashi

AU - Jacquemont, Sébastien

AU - Jahanshad, Neda

AU - Jockwitz, Christiane

AU - Johansson, Stefan

AU - Jönsson, Erik G

AU - Kikuchi, Masataka

AU - Knowles, Emma E M

AU - Kwok, John B

AU - Le Hellard, Stephanie

AU - Linden, David E J

AU - Liu, Jingyu

AU - Lundervold, Arvid

AU - Lundervold, Astri J

AU - Martin, Nicholas G

AU - Mather, Karen A

AU - Mathias, Samuel R

AU - McMahon, Katie L

AU - McRae, Allan F

AU - Medland, Sarah E

AU - Moberget, Torgeir

AU - Moreau, Clara

AU - Morris, Derek W

AU - Mühleisen, Thomas W

AU - Murray, Robin M

AU - Nordvik, Jan E

AU - Nyberg, Lars

AU - Olde Loohuis, Loes M

AU - Ophoff, Roel A

AU - Owen, Michael J

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Peralta, Juan M

AU - Pike, Bruce

AU - Prieto, Carlos

AU - Quinlan, Erin Burke

AU - Reinbold, Céline S

AU - Reis Marques, Tiago

AU - Rucker, James J H

AU - Sachdev, Perminder S

AU - Sando, Sigrid B

AU - Schofield, Peter R

AU - Schork, Andrew J

AU - Schumann, Gunter

AU - Shin, Jean

AU - Shumskaya, Elena

AU - Silva, Ana I

AU - Sisodiya, Sanjay M

AU - Steen, Vidar M

AU - Stein, Dan J

AU - Strike, Lachlan T

AU - Tamnes, Christian K

AU - Teumer, Alexander

AU - Thalamuthu, Anbupalam

AU - Tordesillas-Gutiérrez, Diana

AU - Uhlmann, Anne

AU - Úlfarsson, Magnús Ö

AU - van 't Ent, Dennis

AU - van den Bree, Marianne B M

AU - Vassos, Evangelos

AU - Wen, Wei

AU - Wittfeld, Katharina

AU - Wright, Margaret J

AU - Zayats, Tetyana

AU - Dale, Anders M

AU - Djurovic, Srdjan

AU - Agartz, Ingrid

AU - Westlye, Lars T

AU - Stefánsson, Hreinn

AU - Stefánsson, Kári

AU - Thompson, Paul M

AU - Andreassen, Ole A

AU - Writing Committee for the ENIGMA-CNV Working Group

PY - 2020/4

Y1 - 2020/4

N2 - Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

AB - Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

UR - http://www.scopus.com/inward/record.url?scp=85074651799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074651799&partnerID=8YFLogxK

U2 - 10.1001/jamapsychiatry.2019.3779

DO - 10.1001/jamapsychiatry.2019.3779

M3 - Article

C2 - 31665216

SN - 2168-622X

VL - 77

SP - 420

EP - 430

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 4

ER -

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

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