Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.
Journal: JAMA psychiatry
Volume: 77
Issue: 4
Year of Publication: 2021
Affiliated Institutions:
Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
deCODE Genetics, Reykjavík, Iceland.
Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
University of Melbourne Academic Unit for Psychiatry of Old Age, Kew, Australia.
Institute of Neuroscience and Medicine, Research Centre Juelich, Juelich, Germany.
Umeå Centre for Functional Brain Imaging, Umeå University, Umeå, Sweden.
Mathematics and Statistics, Murdoch University, Perth, Australia.
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville.
Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta.
The School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland.
Interdepartmental Neuroscience Program, University of California, Los Angeles.
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
University Hospital Marqués de Valdecilla, IdahoIVAL, Centre de Investigación Biomédica en Red Salud Mental (CIBERSAM), Santander, Spain.
Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa.
Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
The SFI FutureNeuro Research Centre, Dublin, Ireland.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
Centre for Neuroimaging and Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
Psychological and Social Medicine, Faculty of Medicine, Dresden University of Technology, Dresden, Germany.
Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
Department of Psychology, University of Oslo, Oslo, Norway.
Akershus University Hospital, Lorenskog, Norway.
Neurospin, Le Commissariat à l'énergie atomique et aux énergies alternatives, Université Paris-Saclay, Gif-sur-Yvette, France.
Division of Cerebral Integration, National Institute for Physiological Sciences, Okazaki, Japan.
Boston Children's Hospital, Boston, Massachusetts.
Department of Psychiatry and Psychotherapy, Greifswald, Germany.
Department of Biomedicine, University of Bergen, Bergen, Norway.
Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Japan.
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Genentech, San Francisco, California.
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia's Children's Hospital, Rotterdam, the Netherlands.
Institute of Human Genetics, University of Bonn Medical School, Bonn, Germany.
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
Sainte Justine Hospital Research Center, Montreal, Quebec, Canada.
Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles.
Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
The University of Sydney Central Clinical School, Sydney, Australia.
Norwegian Centre for Mental Disorders Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Herston Imaging Research Facility and School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
The CatoSenteret Rehabilitation Center, Son, Norway.
Center for Neurobehavioral Genetics, University of California, Los Angeles.
Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
Department of Radiology, University of Calgary, Calgary, Alberta, Canada.
Bioinformatics Service, Nucleus, University of Salamanca, Salamanca, Spain.
Centre for Population Neuroscience and Precision Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Department of Biomedicine, University of Basel, Basel, Switzerland.
School of Medical Sciences, University of New South Wales, Sydney, Australia.
Institute for Biological Psychiatry, Roskilde, Denmark.
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
Cardiff University Brain Research Imaging Centre School of Psychology, Cardiff University, Cardiff, United Kingdom.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology and Chalfont Centre for Epilepsy, London, United Kingdom.
Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute, IdahoIVAL, Santander, Spain.
Center for Multimodal Imaging and Genetics, University of California, San Diego.
Abstract summary
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.To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.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.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.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.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.
Authors & Co-authors:
van der Meer Dennis D
Sønderby Ida E IE
Kaufmann Tobias T
Walters G Bragi GB
Abdellaoui Abdel A
Ames David D
Amunts Katrin K
Andersson Micael M
Armstrong Nicola J NJ
Bernard Manon M
Blackburn Nicholas B NB
Blangero John J
Boomsma Dorret I DI
Brodaty Henry H
Brouwer Rachel M RM
Bülow Robin R
Cahn Wiepke W
Calhoun Vince D VD
Caspers Svenja S
Cavalleri Gianpiero L GL
Ching Christopher R K CRK
Cichon Sven S
Ciufolini Simone S
Corvin Aiden A
Crespo-Facorro Benedicto B
Curran Joanne E JE
Dalvie Shareefa S
Dazzan Paola P
de Geus Eco J C EJC
de Zubicaray Greig I GI
de Zwarte Sonja M C SMC
Delanty Norman N
den Braber Anouk A
Desrivieres Sylvane S
Di Forti Marta M
Doherty Joanne L JL
Donohoe Gary G
Ehrlich Stefan S
Eising Else E
Espeseth Thomas T
Fisher Simon E SE
Fladby Tormod T
Frei Oleksandr O
Frouin Vincent V
Fukunaga Masaki M
Gareau Thomas T
Glahn David C DC
Grabe Hans J HJ
Groenewold Nynke A NA
Gústafsson Ómar Ó
Haavik Jan J
Haberg Asta K AK
Hashimoto Ryota R
Hehir-Kwa Jayne Y JY
Hibar Derrek P DP
Hillegers Manon H J MHJ
Hoffmann Per P
Holleran Laurena L
Hottenga Jouke-Jan JJ
Hulshoff Pol Hilleke E HE
Ikeda Masashi M
Jacquemont Sébastien S
Jahanshad Neda N
Jockwitz Christiane C
Johansson Stefan S
Jönsson Erik G EG
Kikuchi Masataka M
Knowles Emma E M EEM
Kwok John B JB
Le Hellard Stephanie S
Linden David E J DEJ
Liu Jingyu J
Lundervold Arvid A
Lundervold Astri J AJ
Martin Nicholas G NG
Mather Karen A KA
Mathias Samuel R SR
McMahon Katie L KL
McRae Allan F AF
Medland Sarah E SE
Moberget Torgeir T
Moreau Clara C
Morris Derek W DW
Mühleisen Thomas W TW
Murray Robin M RM
Nordvik Jan E JE
Nyberg Lars L
Olde Loohuis Loes M LM
Ophoff Roel A RA
Owen Michael J MJ
Paus Tomas T
Pausova Zdenka Z
Peralta Juan M JM
Pike Bruce B
Prieto Carlos C
Quinlan Erin Burke EB
Reinbold Céline S CS
Reis Marques Tiago T
Rucker James J H JJH
Sachdev Perminder S PS
Sando Sigrid B SB
Schofield Peter R PR
Schork Andrew J AJ
Schumann Gunter G
Shin Jean J
Shumskaya Elena E
Silva Ana I AI
Sisodiya Sanjay M SM
Steen Vidar M VM
Stein Dan J DJ
Strike Lachlan T LT
Tamnes Christian K CK
Teumer Alexander A
Thalamuthu Anbupalam A
Tordesillas-Gutiérrez Diana D
Uhlmann Anne A
Úlfarsson Magnús Ö MÖ
van 't Ent Dennis D
van den Bree Marianne B M MBM
Vassos Evangelos E
Wen Wei W
Wittfeld Katharina K
Wright Margaret J MJ
Zayats Tetyana T
Dale Anders M AM
Djurovic Srdjan S
Agartz Ingrid I
Westlye Lars T LT
Stefánsson Hreinn H
Stefánsson Kári K
Thompson Paul M PM
Andreassen Ole A OA
Study Outcome
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