Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Journal: Molecular psychiatry

Volume: 25

Issue: 3

Year of Publication: 2021

Affiliated Institutions:  NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. deCODE Genetics/Amgen, Reykjavik, Iceland. Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, USA. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon , , Lausanne, Switzerland. Biological Psychology, Vrije Universiteit Amsterdam, van Boechorststraat , BT, Amsterdam, The Netherlands. National Ageing Research Institute, Melbourne, Australia. Institute of Neuroscience and Medicine (INM-), Research Centre Juelich, Wilhelm-Johnen-Str., , Juelich, Germany. Umeå Center for Functional Brain Imaging (UFBI), Umeå University, , Umeå, Sweden. Mathematics and Statistics, Murdoch University, Perth, Australia. The Hospital for Sick Children, University of Toronto, Toronto, MG X, Canada. South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, One West University Blvd., , Brownsville, TX, USA. Netherlands Twin Register, Vrije Universiteit, van der Boechorststraat , BT, Amsterdam, Netherlands. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Clinical Science, University of Bergen, Bergen, Norway. Centre for Healthy Brain Ageing and Dementia Collaborative Research Centre, UNSW, Sydney, Australia. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany. The Mind Research Network, The University of New Mexico, Albuquerque, NM, Mexico. The Royal College of Surgeons in Ireland, St Stephen's Green, Dublin , Ireland. Department of Radiology, University of California San Diego, La Jolla, USA. Institute of Neuroscience and Medicine (INM-), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Juelich, Leo-Brandt-Strasse , , Jülich, Germany. Psychosis Studies, Insitute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespingy Park, SE AF, London, United Kingdom. Neuropsychiatric Genetics Research Group, Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin , Ireland. Department of Medicine and Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, , Santander, Spain. Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, USA. Department of Psychiatry and Mental Health, Anzio Road, , Cape Town, South Africa. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, SE AF, London, United Kingdom. Department of Biological Psychology, Behavioral and Movement Sciences, Vrije Universiteit, van der Boechorststraat , BT, Amsterdam, Netherlands. Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. Medical Research Council - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition & Genomics Centre (NICOG) & NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, H TK, Galway, Ireland. LREN - Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, , Dresden, Germany. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan , XD, Nijmegen, Netherlands. NeuroSpin, CEA, Université Paris-Saclay, F-, Gif-sur-Yvette, France. Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan. Yale University School of Medicine, Temple Street, Suite E, , New Haven, Vaud, USA. Department of Psychiatry und Psychotherapy, University Medicine Greifswald, Greifswald, Germany. K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway. Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan. Princess Máxima Center for Pediatric Oncology, Lundlaan , EA, Utrecht, The Netherlands. Dept. of Psychiatry and Psychotherapie, Charite, Humboldt University, Chariteplatz , , Berlin, Germany. Human Genomics Research Group, Department of Biomedicine, University of Basel, Hebelstrasse , , Basel, Switzerland. The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan. Center for Human Development, University of California San Diego, San Diego, CA, USA. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. Department of Genome Informatics, Graduate School of Medicine, Osaka University, -, Yamadaoka, Suita, Osaka, -, Japan. Department of Psychiatry, Yale University, Temple Street, , New Haven, CT, USA. Brain and Mind Centre, University of Sydney, Sydney, Australia. NORMENT - KG Jebsen Centre, Department of Clinical Science, University of Bergen, Jonas Lies veg , , Bergen, Norway. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. The Mind Research Network, Yale Blvd., , Albuquerque, CT, USA. Department of Biomedicine, University of Bergen, , Bergen, Norway. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, , Australia. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St. Stephens Green, D YN, Dublin, Ireland. Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia. Program in Complex Trait Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia. Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands, Oldenaller , HJ, Amsterdam, The Netherlands. CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC, Canada. Departments of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. Sunnaas Rehabilitation Hospital HT, Nesodden, Norway. Center for Neurobehavioral Genetics, University of California, Los Angeles, California, , USA. Rotman Research Institute, University of Toronto, Toronto, MA E, Canada. Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical, Amsterdam, Netherlands. Departments of Radiology & Clinical Neuroscience, University of Calgary, Calgary, TN N, Canada. Bioinformatics Service, Nucleus, University of Salamanca (USAL), , Salamanca, Spain. Centre for Population Neuroscience and Stratified Medicine, Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, SE AF, London, UK. Center for Integrative Genomics, University of Lausanne, Genopode building, CH-, Lausanne, Switzerland. National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom. Orygen, The National Centre of Excellence in Youth Mental Health, Poplar Road, , Parkville, New Mexico, Australia. Neuroscience Research Australia, Randwick, Australia. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK. Dept of Psychiatry, University of Cape Town, Groote Schuur Hospital, Anzio Rd, , Cape Town, South Africa. Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Santander, , Spain. Department of Psychology, Georgia State University, Atlanta, GA, USA. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, SE AF, London, UK. German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Greifswald, Germany. Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. andreassen@medisin.uio.no.

Abstract summary 

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10, 1.7 × 10, 3.5 × 10 and 1.0 × 10, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

Authors & Co-authors:  Sønderby Ida E IE Gústafsson Ómar Ó Doan Nhat Trung NT Hibar Derrek P DP Martin-Brevet Sandra S Abdellaoui Abdel A Ames David D Amunts Katrin K Andersson Michael M Armstrong Nicola J NJ Bernard Manon M Blackburn Nicholas N Blangero John J Boomsma Dorret I DI Bralten Janita J Brattbak Hans-Richard HR Brodaty Henry H Brouwer Rachel M RM Bülow Robin R Calhoun Vince V Caspers Svenja S Cavalleri Gianpiero G Chen Chi-Hua CH Cichon Sven S Ciufolini Simone S Corvin Aiden A 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 Delanty Norman N den Braber Anouk A Desrivières Sylvane S Donohoe Gary G Draganski Bogdan B Ehrlich Stefan S Espeseth Thomas T Fisher Simon E SE Franke Barbara B Frouin Vincent V Fukunaga Masaki M Gareau Thomas T Glahn David C DC Grabe Hans H Groenewold Nynke A NA Haavik Jan J Håberg Asta A Hashimoto Ryota R Hehir-Kwa Jayne Y JY Heinz Andreas A Hillegers Manon H J MHJ Hoffmann Per P Holleran Laurena L Hottenga Jouke-Jan JJ Hulshoff Hilleke E HE Ikeda Masashi M Jahanshad Neda N Jernigan Terry T Jockwitz Christiane C Johansson Stefan S Jonsdottir Gudrun A GA Jönsson Erik G EG Kahn Rene R Kaufmann Tobias T Kelly Sinead S Kikuchi Masataka M Knowles Emma E M EEM Kolskår Knut K KK Kwok John B JB Hellard Stephanie Le SL Leu Costin C Liu Jingyu J Lundervold Astri J AJ Lundervold Arvid A Martin Nicholas G NG Mather Karen K Mathias Samuel R SR McCormack Mark M McMahon Katie L KL McRae Allan A Milaneschi Yuri Y Moreau Clara C Morris Derek D Mothersill David D Mühleisen Thomas W TW Murray Robin R Nordvik Jan E JE Nyberg Lars L Olde Loohuis Loes M LM Ophoff Roel R Paus Tomas T Pausova Zdenka Z Penninx Brenda B Peralta Juan M JM Pike Bruce B Prieto Carlos C Pudas Sara S Quinlan Erin E Quintana Daniel S DS Reinbold Céline S CS Marques Tiago Reis TR Reymond Alexandre A Richard Genevieve G Rodriguez-Herreros Borja B Roiz-Santiañez Roberto R Rokicki Jarek J Rucker James J Sachdev Perminder P Sanders Anne-Marthe AM Sando Sigrid B SB Schmaal Lianne L Schofield Peter R PR Schork Andrew J AJ Schumann Gunter G Shin Jean J Shumskaya Elena E Sisodiya Sanjay S Steen Vidar M VM Stein Dan J DJ Steinberg Stacy S Strike Lachlan L Teumer Alexander A Thalamuthu Anbu A Tordesillas-Gutierrez Diana D Turner Jessica J Ueland Torill T Uhlmann Anne A Ulfarsson Magnus O MO van 't Ent Dennis D van der Meer Dennis D van Haren Neeltje E M NEM Vaskinn Anja A Vassos Evangelos E Walters G Bragi GB Wang Yunpeng Y Wen Wei W Whelan Christopher D CD Wittfeld Katharina K Wright Margie M Yamamori Hidenaga H Zayats Tetyana T Agartz Ingrid I Westlye Lars T LT Jacquemont Sébastien S Djurovic Srdjan S Stefánsson Hreinn H Stefánsson Kári K Thompson Paul P Andreassen Ole A OA

Study Outcome 

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Citations :  Kirov G, Rees E, Walters J. What a psychiatrist needs to know about copy number variants. Br J Psych Adv. 2015;21:157–63.
Authors :  154
Identifiers
Doi : 10.1038/s41380-018-0118-1
SSN : 1476-5578
Study Population
Male,Female
Mesh Terms
Adult
Other Terms
Study Design
Cross Sectional Study
Study Approach
Country of Study
Publication Country
England