Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
ENIGMA-CNV Working Group
(2020) JAMA Psychiatry, volume 77, issue 4, pp. 420 - 430
(Article)
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
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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.
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Keywords: Psychiatry and Mental health, Journal Article
ISSN: 2168-622X
Publisher: American Medical Association
Note: Funding Information: 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 Information: Funding/Support: This study is supported in part Funding Information: 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. Funding Information: 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. Funding Information: 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). Funding Information: 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- Funding Information: 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). Funding Information: 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. Funding Information: 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. Funding Information: 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. Funding Information: MCIC/COBRE is funded by the National Institutes of Health studies R01EB006841, P20GM103472, and P30GM122734. Funding Information: 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. Funding Information: 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. Funding Information: EPIGEN-Dublin: The EPIGEN-Dublin cohort was supported by a Science Foundation Ireland Research Frontiers Programme award (08/RFP/GEN1538). Funding Information: FP7 funded grant no. 602450 (IMAGEMEND) and EU funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC). Funding Information: 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. Funding Information: 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). Funding Information: 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. Funding Information: 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. Funding Information: 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. Funding Information: 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. Funding Information: 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. Funding Information: 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. Funding Information: Sydney MAS: The Sydney Memory and Aging Study (Sydney MAS) is funded by National and Health Medical Research Council (NHMRC) Program and Project Grants (ID350833, ID568969, ID109308). We also thank the Sydney MAS participants and the Research Team. Funding Information: 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. Funding Information: 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). Funding Information: SYS: The SYS Study is supported by Canadian Institutes of Health Research. Funding Information: 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). Funding Information: ENIGMA: ENIGMA is supported in part by NIH grants U54 EB20403, R01MH116147, and R56AG058854. Funding Information: 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. Publisher Copyright: © 2019 American Medical Association. All rights reserved.
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