1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.
Journal: Translational psychiatry
Volume: 11
Issue: 1
Year of Publication: 2021
Affiliated Institutions: NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. i.e.sonderby@medisin.uio.no. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Sainte Justine Hospital Research Center, Montreal, Quebec, Canada. deCODE Genetics (Amgen), Reykjavík, Iceland. Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. 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, INM-, Research Centre Jülich, Jülich, 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, USA. 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, University Medical Center Brain Center, Utrecht University, Utrecht, the Netherlands. Institute 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, USA. Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles, USA. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. University Hospital Marqués de Valdecilla, IDIVAL, Centro de Investigación Biomédica en Red Salud Mental (CIBERSAM), Santander, Spain. Center for Multimodal Imaging and Genetics, University of California, San Diego, USA. Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa. Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. Faculty of Health, Queensland University of Technology, Brisbane, Australia. Social, Genetic & Developmental Psychiatry Centre, 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. Laboratory for Research in Neuroimaging LREN, Centre for Research in Neurosciences, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. Division of Psychological and Social Medicine, Faculty of Medicine, TU Dresden, Dresden, Germany. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands. Department of Psychology, University of Oslo, Oslo, Norway. Signal Transduction, H. Lundbeck A/S, Ottiliavej , DK-, Valby, Denmark. Department of Neurology, Akershus University Hospital, , Nordbyhagen, Norway. Université Paris-Saclay, CEA, Neurospin, , Gif-sur-Yvette, France. Division of Cerebral Integration, National Institute for Physiological Sciences, Okazaki, Japan. Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. Boston Children's Hospital, Boston, Massachusetts, USA. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 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 Màxima Center for Pediatric Oncology, Utrecht, the Netherlands. Genentech, Inc., South San Francisco, , CA, USA. Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, Rotterdam, the Netherlands. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. Psychology Department, Yale University, New Haven, CT, USA. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan. Department of Clinical Science, University of Bergen, Bergen, Norway. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden. Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark. Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan. Norwegian Centre for Mental Disorders Research, Department of Clinical Science, University of Bergen, Bergen, Norway. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 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. Service des Troubles du Spectre de l'Autisme et apparentés, Lausanne University Hospital, Lausanne, Switzerland. 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. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. The CatoSenteret Rehabilitation Center, Son, Norway. Center for Neurobehavioral Genetics, University of California, Los Angeles, USA. Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada. Departments of Radiology and Clinical Neurosciences, 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. Department of Psychosis, Institute of Psychiatry, Psychology & Neuroscience, Kings College, London, United Kingdom. Institute of Psychiatry, Psychology and Neuroscience, London, London, United Kingdom. Neuroscience Research Australia, Sydney, Australia. Institute of Biological Psychiatry, Roskilde, Denmark. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WCN BG, UK. South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa. Queensland Brain Institute, University of Queensland, Brisbane, Australia. VIB Center for Brain & Disease Research, Stem Cell and Developmental Neurobiology Lab, Leuven, Belgium. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. VIB-KU Leuven Center for Brain & Disease Research, , Leuven, Belgium. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Abstract summary
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.Authors & Co-authors: Sønderby Ida E IE van der Meer Dennis D Moreau Clara C Kaufmann Tobias T Walters G Bragi GB Ellegaard Maria M 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 Bøen Rune R Cahn Wiepke W Calhoun Vince D VD Caspers Svenja S Ching Christopher R K CRK Cichon Sven S Ciufolini Simone S Crespo-Facorro Benedicto B Curran Joanne E JE Dale Anders M AM Dalvie Shareefa S Dazzan Paola P de Geus Eco J C EJC de Zubicaray Greig I GI de Zwarte Sonja M C SMC Desrivieres Sylvane S Doherty Joanne L JL Donohoe Gary G Draganski Bogdan B Ehrlich Stefan S Eising Else E Espeseth Thomas T Fejgin Kim K Fisher Simon E SE Fladby Tormod T Frei Oleksandr O Frouin Vincent V Fukunaga Masaki M Gareau Thomas T Ge Tian T Glahn David C DC Grabe Hans J HJ Groenewold Nynke A NA Gústafsson Ómar Ó Haavik Jan J Haberg Asta K AK Hall Jeremy J Hashimoto Ryota R Hehir-Kwa Jayne Y JY Hibar Derrek P DP Hillegers Manon H J MHJ Hoffmann Per P Holleran Laurena L Holmes Avram J AJ Homuth Georg G Hottenga Jouke-Jan JJ Hulshoff Pol Hilleke E HE Ikeda Masashi M Jahanshad Neda N Jockwitz Christiane C Johansson Stefan S Jönsson Erik G EG Jørgensen Niklas R NR Kikuchi Masataka M Knowles Emma E M EEM Kumar Kuldeep K Le Hellard Stephanie S Leu Costin C Linden David E J DEJ Liu Jingyu J Lundervold Arvid A Lundervold Astri Johansen AJ Maillard Anne M AM Martin Nicholas G NG Martin-Brevet Sandra S Mather Karen A KA Mathias Samuel R SR McMahon Katie L KL McRae Allan F AF Medland Sarah E SE Meyer-Lindenberg Andreas A Moberget Torgeir T Modenato Claudia C Sánchez Jennifer Monereo JM Morris Derek W DW Mühleisen Thomas W TW Murray Robin M RM Nielsen Jacob J Nordvik Jan E JE Nyberg Lars L Loohuis Loes M Olde LMO Ophoff Roel A RA Owen Michael J MJ Paus Tomas T Pausova Zdenka Z Peralta Juan M JM Pike G Bruce GB Prieto Carlos C Quinlan Erin B EB Reinbold Céline S CS Marques Tiago Reis TR 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 Suzuki Ikuo K IK Tamnes Christian K CK Teumer Alexander A Thalamuthu Anbupalam A Tordesillas-Gutiérrez Diana D Uhlmann Anne A Ulfarsson Magnus O MO van 't Ent Dennis D van den Bree Marianne B M MBM Vanderhaeghen Pierre P Vassos Evangelos E Wen Wei W Wittfeld Katharina K Wright Margaret J MJ Agartz Ingrid I Djurovic Srdjan S Westlye Lars T LT Stefansson Hreinn H Stefansson Kari K Jacquemont Sébastien S Thompson Paul M PM Andreassen Ole A OA
Study Outcome
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Citations : Toga AW, Thompson PM. Genetics of brain structure and intelligence. Annu. Rev. Neurosci. 2005;28:1–23. doi: 10.1146/annurev.neuro.28.061604.135655.Authors : 145
Identifiers
Doi : 182SSN : 2158-3188