1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

• Type of Material: Article
• Authors: Ida E Sonderby, University of Oslo; Dennis van der Meer, University of Oslo; Clara Moreau, Sainte Justine Hospital Research Center; Tobias Kaufmann, University of Oslo; Bragi Walters, deCODE Genetics (Amgen); Maria Ellegaard, Copenhagen University Hospital; Abdel Abdellaoui, University of Amsterdam; David Ames, University of Melbourne; Katrin Amunts, Research Centre Jülich; Micael Andersson, Umea University; Nicola J Armstrong, Murdoch University; Manon Bernard, Hospital for Sick Children; Nicholas B Blackburn, University of Texas Rio Grande Valley; John Blangero, University of Texas Rio Grande Valley; Dorret I Boomsma, Vrije Universiteit Amsterdam; Henry Brodaty, University of New South Wales; Rachel M Brouwer, Utrecht University; Robin Bülow, Univ Med Greifswald; Rune Bøen, University of Oslo; Wiepke Cahn, Utrecht University; Vince Calhoun, Emory University; Svenja Caspers, Research Centre Jülich; Christopher RK Ching, University of Southern California, Los Angeles; Sven Cichon, Research Centre Jülich; Simone Ciufolini, King’s College London; Benedicto Crespo-Facorro, University Hospital Marqués de Valdecilla; Joanne E Curran, University of Texas Rio Grande Valley; Anders M Dale, University of California San Diego; Shareefa Dalvie, University of Cape Town; Paola Dazzan, King’s College London; Eco JC de Geus, Vrije Universiteit Amsterdam; Greig I de Zubicaray, Queensland University of Technology; Sonja MC de Zwarte, Utrecht University; Sylvane Desrivieres, King’s College London; Joanne L Doherty, Cardiff University; Gary Donohoe, National University of Ireland Galway; Bogdan Draganski, Lausanne University Hospital; Stefan Ehrlich, Technische Universitat Dresden; Else Eising, Max Planck Institute for Psycholinguistics; Thomas Espeseth, University of Oslo; Kim Fejgin, H. Lundbeck A/S, Ottiliavej 9; Simon E Fisher, Max Planck Institute for Psycholinguistics; Tormod Fladby, University of Oslo; Oleksandr Frei, University of Oslo; Vincent Frouin, Université Paris-Saclay, CEA, Neurospin; Masaki Fukunaga, Natl Inst Physiol Sci; Thomas Gareau, H Lundbeck & Co AS; Tian Ge, Massachusetts General Hospital; David C Glahn, Boston Children’s Hospital; Hans J Grabe, University Medicine Greifswald; Nynke A Groenewold, University of Cape Town; Ómar Gústafsson, deCODE Genetics (Amgen); Jan Haavik, University of Bergen; Asta K Haberg, Norwegian University of Science and Technology; Jeremy Hall, Cardiff University; Ryota Hashimoto, National Center of Neurology and Psychiatry; Jayne Y Hehir-Kwa, Princess Maxima Ctr Pediat Oncol; Derreck P Hibar, Genencor Inc; Manon HJ Hillegers, Erasmus MC Sophia; Per Hoffmann, University Hospital Basel; Laurena Holleran, National University of Ireland Galway; Avram J Holmes, Yale University; Georg Homuth, University Medicine Greifswald; Jouke-Jan Hottenga, Vrije Universiteit Amsterdam; Hileke E Hulshoff Pol, Utrecht University; Masashi Ikeda, Fujita Health University School of Medicine; Neda Jahanshad, University of Southern California; Christiane Jockwitz, Research Centre Jülich; Stefan Johansson, University of Bergen; Erik G Jönsson, Karolinska Institutet; Niklas R Jørgensen, Copenhagen University Hospital Rigshospitalet; Masataka Kikuchi, Osaka University; Emma EM Knowles, Boston Children’s Hospital; Kuldeep Kumar, Sainte Justine Hospital Research Center; Stephanie Le Hellard, University of Bergen; Costin Leu, Broad Institute of MIT and Harvard; David EJ Linden, Maastricht University; Jingyu Liu, Emory University; Arvid Lundervold, University of Bergen; Astri Johansen Lundervold, University of Bergen; Anne M Maillard, Lausanne University Hospital; Nicholas G Martin, QIMR Berghofer Medical Research Institute; Sandra Martin-Brevet, Lausanne University Hospital; Karen A Mather, University of New South Wales, Sydney; Samuel R Mathias, Boston Children’s Hospital; Katie L McMahon, Queensland University of Technology; Allan F McRae, University of Queensland; Sarah E Medland, QIMR Berghofer Medical Research Institute; Andreas Meyer-Lindenberg, University of Heidelberg; Torgeir Moberget, University of Oslo; Claudia Modenato, Lausanne University Hospital; Jennifer Monereo Sánchez, Maastricht University; Derek W Morris, National University of Ireland Galway; Thomas W Muehleisen, Research Centre Jülich; Robin M Murray, King’s College London; Jacob Nielsen, H. Lundbeck A/S, Ottiliavej 9; Jan E Nordvik, The CatoSenteret Rehabilitation Center; Lars Nyberg, Umeå University; Loes MO Loohuis, University of California Los Angeles; Roel A Ophoff, University of California Los Angeles; Michael J Owen, Cardiff University; Tomas Paus, Holland Bloorview Kids Rehabilitation Hospital; Zdenka Pausova, Hospital for Sick Children; Juan M Peralta, University of Texas Rio Grande Valley; Bruce G Pike, University of Calgary; Carlos Prieto, University of Salamanca; Erin B Quinlan, King’s College London; Céline S Reinbold, University of Basel; Tiago Reis Marques, Kings College, London; James JH Rucker, Institute of Psychiatry, Psychology and Neuroscience, London; Perminder S Sachdev, University of New South Wales; Sigrid B Sando, Norwegian University of Science and Technology; Peter R Schofield, Neuroscience Research Australia; Andrew J Schork, Institute of Biological Psychiatry, Roskilde; Gunter Schumann, King’s College London; Jean Shin, Hospital for Sick Children, Toronto; Elena Shumskaya, Radboud University Nijmegen; Ana I Silva, Maastricht University; Sanjay M Sisodiya, UCL Queen Square Institute of Neurology; Vidar M Steen, University of Bergen; Dan J Stein, University of Cape Town; Lachlan T Strike, University of Queensland; Ikuo K Suzuki, Stem Cell and Developmental Neurobiology Lab, Leuven; Christian K Tamnes, University of Oslo; Alexander Teumer, University Medicine Greifswald; Anbupalam Thalamuthu, University of New South Wales; Diana Tordesillas-Gutierrez, University Hospital Marqués de Valdecilla; Anne Uhlmann, University of Cape Town; Magnus O Ulfarsson, deCODE Genetics (Amgen); Dennis van 't Ent, Vrije Universiteit Amsterdam; Marianne BM van den Bree, Cardiff University; Pierre Vanderhaeghen, VIB-KU Leuven; Evangelos Vassos, King’s College London; Wei Wen, University of New South Wales; Katharina Wittfeld, University Medicine Greifswald; Margaret J Wright, University of Queensland; Ingrid Agartz, Karolinska Institutet; Srdjan Djurovic, Oslo University Hospital; Lars T Westlye, University of Oslo; Hreinn Stefansson, DeCODE Genet Amgen; Kari Stefansson, DeCODE Genet Amgen; Sébastien Jacquemont, Sainte Justine Hospital Research Center, Montreal; Paul M Thompson, University of Southern California; Ole A Andreassen, University of Oslo
• Language: English
• Date: 2021-03-22
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-021-01213-0
• Title of Journal or Parent Work: TRANSLATIONAL PSYCHIATRY
• Volume: 11
• Issue: 1
• Start Page: 182
• End Page: 182
• Keywords: ABNORMALITIES; MICRODELETIONS; Science & Technology; Psychiatry; EXPANSION; GENOME; MICRODUPLICATION; REARRANGEMENTS; PHENOTYPE; Life Sciences & Biomedicine; CHROMOSOME 1Q21.1; BRAIN; DUPLICATIONS
• Research Categories: Health Sciences, Radiology; Health Sciences, Mental Health

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.