Translational Psychiatry (Mar 2021)
1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- Ida E. Sønderby,
- Dennis van der Meer,
- Clara Moreau,
- Tobias Kaufmann,
- G. Bragi Walters,
- Maria Ellegaard,
- Abdel Abdellaoui,
- David Ames,
- Katrin Amunts,
- Micael Andersson,
- Nicola J. Armstrong,
- Manon Bernard,
- Nicholas B. Blackburn,
- John Blangero,
- Dorret I. Boomsma,
- Henry Brodaty,
- Rachel M. Brouwer,
- Robin Bülow,
- Rune Bøen,
- Wiepke Cahn,
- Vince D. Calhoun,
- Svenja Caspers,
- Christopher R. K. Ching,
- Sven Cichon,
- Simone Ciufolini,
- Benedicto Crespo-Facorro,
- Joanne E. Curran,
- Anders M. Dale,
- Shareefa Dalvie,
- Paola Dazzan,
- Eco J. C. de Geus,
- Greig I. de Zubicaray,
- Sonja M. C. de Zwarte,
- Sylvane Desrivieres,
- Joanne L. Doherty,
- Gary Donohoe,
- Bogdan Draganski,
- Stefan Ehrlich,
- Else Eising,
- Thomas Espeseth,
- Kim Fejgin,
- Simon E. Fisher,
- Tormod Fladby,
- Oleksandr Frei,
- Vincent Frouin,
- Masaki Fukunaga,
- Thomas Gareau,
- Tian Ge,
- David C. Glahn,
- Hans J. Grabe,
- Nynke A. Groenewold,
- Ómar Gústafsson,
- Jan Haavik,
- Asta K. Haberg,
- Jeremy Hall,
- Ryota Hashimoto,
- Jayne Y. Hehir-Kwa,
- Derrek P. Hibar,
- Manon H. J. Hillegers,
- Per Hoffmann,
- Laurena Holleran,
- Avram J. Holmes,
- Georg Homuth,
- Jouke-Jan Hottenga,
- Hilleke E. Hulshoff Pol,
- Masashi Ikeda,
- Neda Jahanshad,
- Christiane Jockwitz,
- Stefan Johansson,
- Erik G. Jönsson,
- Niklas R. Jørgensen,
- Masataka Kikuchi,
- Emma E. M. Knowles,
- Kuldeep Kumar,
- Stephanie Le Hellard,
- Costin Leu,
- David E. J. Linden,
- Jingyu Liu,
- Arvid Lundervold,
- Astri Johansen Lundervold,
- Anne M. Maillard,
- Nicholas G. Martin,
- Sandra Martin-Brevet,
- Karen A. Mather,
- Samuel R. Mathias,
- Katie L. McMahon,
- Allan F. McRae,
- Sarah E. Medland,
- Andreas Meyer-Lindenberg,
- Torgeir Moberget,
- Claudia Modenato,
- Jennifer Monereo Sánchez,
- Derek W. Morris,
- Thomas W. Mühleisen,
- Robin M. Murray,
- Jacob Nielsen,
- Jan E. Nordvik,
- Lars Nyberg,
- Loes M. Olde Loohuis,
- Roel A. Ophoff,
- Michael J. Owen,
- Tomas Paus,
- Zdenka Pausova,
- Juan M. Peralta,
- G. Bruce Pike,
- Carlos Prieto,
- Erin B. Quinlan,
- Céline S. Reinbold,
- Tiago Reis Marques,
- James J. H. Rucker,
- Perminder S. Sachdev,
- Sigrid B. Sando,
- Peter R. Schofield,
- Andrew J. Schork,
- Gunter Schumann,
- Jean Shin,
- Elena Shumskaya,
- Ana I. Silva,
- Sanjay M. Sisodiya,
- Vidar M. Steen,
- Dan J. Stein,
- Lachlan T. Strike,
- Ikuo K. Suzuki,
- Christian K. Tamnes,
- Alexander Teumer,
- Anbupalam Thalamuthu,
- Diana Tordesillas-Gutiérrez,
- Anne Uhlmann,
- Magnus O. Ulfarsson,
- Dennis van ‘t Ent,
- Marianne B. M. van den Bree,
- Pierre Vanderhaeghen,
- Evangelos Vassos,
- Wei Wen,
- Katharina Wittfeld,
- Margaret J. Wright,
- Ingrid Agartz,
- Srdjan Djurovic,
- Lars T. Westlye,
- Hreinn Stefansson,
- Kari Stefansson,
- Sébastien Jacquemont,
- Paul M. Thompson,
- Ole A. Andreassen,
- for the ENIGMA-CNV working group
Affiliations
- Ida E. Sønderby
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Dennis van der Meer
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Clara Moreau
- Sainte Justine Hospital Research Center, Montreal
- Tobias Kaufmann
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- G. Bragi Walters
- deCODE Genetics (Amgen)
- Maria Ellegaard
- Department of Clinical Biochemistry, Copenhagen University Hospital
- Abdel Abdellaoui
- Department of Psychiatry, Amsterdam UMC, University of Amsterdam
- David Ames
- University of Melbourne Academic Unit for Psychiatry of Old Age
- Katrin Amunts
- Institute of Neuroscience and Medicine, INM-1, Research Centre Jülich
- Micael Andersson
- Umeå Centre for Functional Brain Imaging, Umeå University
- Nicola J. Armstrong
- Mathematics and Statistics, Murdoch University
- Manon Bernard
- Research Institute, Hospital for Sick Children
- Nicholas B. Blackburn
- South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley
- John Blangero
- South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley
- Dorret I. Boomsma
- Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam
- Henry Brodaty
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Rachel M. Brouwer
- Department of Psychiatry, University Medical Center Brain Center, Utrecht University
- Robin Bülow
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald
- Rune Bøen
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Wiepke Cahn
- Department of Psychiatry, University Medical Center Brain Center, Utrecht University
- Vince D. Calhoun
- Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University
- Svenja Caspers
- Institute of Neuroscience and Medicine, INM-1, Research Centre Jülich
- Christopher R. K. Ching
- Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California
- Sven Cichon
- Institute of Neuroscience and Medicine, INM-1, Research Centre Jülich
- Simone Ciufolini
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Benedicto Crespo-Facorro
- University Hospital Marqués de Valdecilla, IDIVAL, Centro de Investigación Biomédica en Red Salud Mental (CIBERSAM)
- Joanne E. Curran
- South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley
- Anders M. Dale
- Center for Multimodal Imaging and Genetics, University of California
- Shareefa Dalvie
- Department of Psychiatry and Neuroscience Institute, University of Cape Town
- Paola Dazzan
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Eco J. C. de Geus
- Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam
- Greig I. de Zubicaray
- Faculty of Health, Queensland University of Technology
- Sonja M. C. de Zwarte
- Department of Psychiatry, University Medical Center Brain Center, Utrecht University
- Sylvane Desrivieres
- Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Joanne L. Doherty
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Gary Donohoe
- Centre for Neuroimaging and Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway
- Bogdan Draganski
- Laboratory for Research in Neuroimaging LREN, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne
- Stefan Ehrlich
- Division of Psychological and Social Medicine, Faculty of Medicine, TU Dresden
- Else Eising
- Language and Genetics Department, Max Planck Institute for Psycholinguistics
- Thomas Espeseth
- Department of Psychology, University of Oslo
- Kim Fejgin
- Signal Transduction, H. Lundbeck A/S
- Simon E. Fisher
- Language and Genetics Department, Max Planck Institute for Psycholinguistics
- Tormod Fladby
- Department of Neurology, Akershus University Hospital
- Oleksandr Frei
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Vincent Frouin
- Université Paris-Saclay, CEA, Neurospin
- Masaki Fukunaga
- Division of Cerebral Integration, National Institute for Physiological Sciences
- Thomas Gareau
- Université Paris-Saclay, CEA, Neurospin
- Tian Ge
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
- David C. Glahn
- Boston Children’s Hospital
- Hans J. Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald
- Nynke A. Groenewold
- Department of Psychiatry and Neuroscience Institute, University of Cape Town
- Ómar Gústafsson
- deCODE Genetics (Amgen)
- Jan Haavik
- Department of Biomedicine, University of Bergen
- Asta K. Haberg
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology
- Jeremy Hall
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Ryota Hashimoto
- Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry
- Jayne Y. Hehir-Kwa
- Princess Màxima Center for Pediatric Oncology
- Derrek P. Hibar
- Genentech, Inc.
- Manon H. J. Hillegers
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia
- Per Hoffmann
- Institute of Medical Genetics and Pathology, University Hospital Basel
- Laurena Holleran
- Centre for Neuroimaging and Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway
- Avram J. Holmes
- Psychology Department, Yale University
- Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald
- Jouke-Jan Hottenga
- Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam
- Hilleke E. Hulshoff Pol
- Department of Psychiatry, University Medical Center Brain Center, Utrecht University
- Masashi Ikeda
- Department of Psychiatry, Fujita Health University School of Medicine
- Neda Jahanshad
- Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California
- Christiane Jockwitz
- Institute of Neuroscience and Medicine, INM-1, Research Centre Jülich
- Stefan Johansson
- Department of Clinical Science, University of Bergen
- Erik G. Jönsson
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm Region
- Niklas R. Jørgensen
- Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet
- Masataka Kikuchi
- Department of Genome Informatics, Graduate School of Medicine, Osaka University
- Emma E. M. Knowles
- Boston Children’s Hospital
- Kuldeep Kumar
- Sainte Justine Hospital Research Center, Montreal
- Stephanie Le Hellard
- Norwegian Centre for Mental Disorders Research, Department of Clinical Science, University of Bergen
- Costin Leu
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
- David E. J. Linden
- School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University
- Jingyu Liu
- Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University
- Arvid Lundervold
- Department of Biomedicine, University of Bergen
- Astri Johansen Lundervold
- Department of Biological and Medical Psychology, University of Bergen
- Anne M. Maillard
- Service des Troubles du Spectre de l’Autisme et apparentés, Lausanne University Hospital
- Nicholas G. Martin
- Genetic Epidemiology, QIMR Berghofer Medical Research Institute
- Sandra Martin-Brevet
- Laboratory for Research in Neuroimaging LREN, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne
- Karen A. Mather
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Samuel R. Mathias
- Boston Children’s Hospital
- Katie L. McMahon
- Herston Imaging Research Facility and School of Clinical Sciences, Queensland University of Technology
- Allan F. McRae
- Institute for Molecular Bioscience, University of Queensland
- Sarah E. Medland
- Psychiatric Genetics, QIMR Berghofer Medical Research Institute
- Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Torgeir Moberget
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Claudia Modenato
- Laboratory for Research in Neuroimaging LREN, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne
- Jennifer Monereo Sánchez
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center
- Derek W. Morris
- Centre for Neuroimaging and Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway
- Thomas W. Mühleisen
- Institute of Neuroscience and Medicine, INM-1, Research Centre Jülich
- Robin M. Murray
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Jacob Nielsen
- Signal Transduction, H. Lundbeck A/S
- Jan E. Nordvik
- The CatoSenteret Rehabilitation Center
- Lars Nyberg
- Umeå Centre for Functional Brain Imaging, Umeå University
- Loes M. Olde Loohuis
- Center for Neurobehavioral Genetics, University of California
- Roel A. Ophoff
- Center for Neurobehavioral Genetics, University of California
- Michael J. Owen
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Tomas Paus
- Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto
- Zdenka Pausova
- Research Institute, Hospital for Sick Children
- Juan M. Peralta
- South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley
- G. Bruce Pike
- Departments of Radiology and Clinical Neurosciences, University of Calgary
- Carlos Prieto
- Bioinformatics Service, Nucleus, University of Salamanca
- Erin B. Quinlan
- Centre for Population Neuroscience and Precision Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Céline S. Reinbold
- Department of Biomedicine, University of Basel
- Tiago Reis Marques
- Department of Psychosis, Institute of Psychiatry, Psychology & Neuroscience, Kings College
- James J. H. Rucker
- Institute of Psychiatry, Psychology and Neuroscience, London
- Perminder S. Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Sigrid B. Sando
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology
- Peter R. Schofield
- Neuroscience Research Australia
- Andrew J. Schork
- Institute of Biological Psychiatry
- Gunter Schumann
- Centre for Population Neuroscience and Precision Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Jean Shin
- Research Institute, Hospital for Sick Children
- Elena Shumskaya
- Donders Institute for Brain, Cognition and Behaviour, Radboud University
- Ana I. Silva
- School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University
- Sanjay M. Sisodiya
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology
- Vidar M. Steen
- Norwegian Centre for Mental Disorders Research, Department of Clinical Science, University of Bergen
- Dan J. Stein
- South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town
- Lachlan T. Strike
- Queensland Brain Institute, University of Queensland
- Ikuo K. Suzuki
- VIB Center for Brain & Disease Research, Stem Cell and Developmental Neurobiology Lab
- Christian K. Tamnes
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald
- Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Diana Tordesillas-Gutiérrez
- University Hospital Marqués de Valdecilla, IDIVAL, Centro de Investigación Biomédica en Red Salud Mental (CIBERSAM)
- Anne Uhlmann
- Department of Psychiatry and Neuroscience Institute, University of Cape Town
- Magnus O. Ulfarsson
- deCODE Genetics (Amgen)
- Dennis van ‘t Ent
- Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam
- Marianne B. M. van den Bree
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
- Pierre Vanderhaeghen
- VIB-KU Leuven Center for Brain & Disease Research
- Evangelos Vassos
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Wei Wen
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Katharina Wittfeld
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald
- Margaret J. Wright
- Queensland Brain Institute, University of Queensland
- Ingrid Agartz
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm Region
- Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital
- Lars T. Westlye
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- Hreinn Stefansson
- deCODE Genetics (Amgen)
- Kari Stefansson
- deCODE Genetics (Amgen)
- Sébastien Jacquemont
- Sainte Justine Hospital Research Center, Montreal
- Paul M. Thompson
- Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California
- Ole A. Andreassen
- NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo
- for the ENIGMA-CNV working group
- DOI
- https://doi.org/10.1038/s41398-021-01213-0
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 16
Abstract
Abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
