1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
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Published:2021-03-22
Issue:1
Volume:11
Page:
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ISSN:2158-3188
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Container-title:Translational Psychiatry
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language:en
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Short-container-title:Transl Psychiatry
Author:
Sønderby Ida E.ORCID, , van der Meer DennisORCID, Moreau ClaraORCID, Kaufmann TobiasORCID, Walters G. BragiORCID, Ellegaard Maria, Abdellaoui AbdelORCID, Ames David, Amunts KatrinORCID, Andersson Micael, Armstrong Nicola J.ORCID, Bernard Manon, Blackburn Nicholas B.ORCID, Blangero JohnORCID, Boomsma Dorret I.ORCID, Brodaty HenryORCID, Brouwer Rachel M., Bülow RobinORCID, Bøen Rune, Cahn WiepkeORCID, Calhoun Vince D., Caspers Svenja, Ching Christopher R. K., Cichon SvenORCID, Ciufolini Simone, Crespo-Facorro Benedicto, Curran Joanne E., Dale Anders M., Dalvie ShareefaORCID, Dazzan PaolaORCID, de Geus Eco J. C.ORCID, de Zubicaray Greig I.ORCID, de Zwarte Sonja M. C., Desrivieres SylvaneORCID, Doherty Joanne L., Donohoe Gary, Draganski BogdanORCID, Ehrlich Stefan, Eising ElseORCID, Espeseth Thomas, Fejgin Kim, Fisher Simon E.ORCID, Fladby Tormod, Frei Oleksandr, Frouin VincentORCID, Fukunaga Masaki, Gareau Thomas, Ge Tian, Glahn David C., Grabe Hans J.ORCID, Groenewold Nynke A., Gústafsson Ómar, Haavik JanORCID, Haberg Asta K., Hall JeremyORCID, Hashimoto Ryota, Hehir-Kwa Jayne Y., Hibar Derrek P., Hillegers Manon H. J.ORCID, Hoffmann PerORCID, Holleran Laurena, Holmes Avram J.ORCID, Homuth Georg, Hottenga Jouke-JanORCID, Hulshoff Pol Hilleke E., Ikeda MasashiORCID, Jahanshad NedaORCID, Jockwitz Christiane, Johansson StefanORCID, Jönsson Erik G., Jørgensen Niklas R., Kikuchi MasatakaORCID, Knowles Emma E. M., Kumar KuldeepORCID, Le Hellard StephanieORCID, Leu Costin, Linden David E. J., Liu JingyuORCID, Lundervold Arvid, Lundervold Astri JohansenORCID, Maillard Anne M.ORCID, Martin Nicholas G., Martin-Brevet Sandra, Mather Karen A.ORCID, Mathias Samuel R., McMahon Katie L.ORCID, McRae Allan F.ORCID, Medland Sarah E.ORCID, Meyer-Lindenberg Andreas, Moberget Torgeir, Modenato ClaudiaORCID, Sánchez Jennifer MonereoORCID, Morris Derek W.ORCID, Mühleisen Thomas W.ORCID, Murray Robin M.ORCID, Nielsen Jacob, Nordvik Jan E., Nyberg Lars, Loohuis Loes M. OldeORCID, Ophoff Roel A.ORCID, Owen Michael J.ORCID, Paus TomasORCID, Pausova ZdenkaORCID, Peralta Juan M.ORCID, Pike G. BruceORCID, Prieto CarlosORCID, Quinlan Erin B.ORCID, Reinbold Céline S., Marques Tiago ReisORCID, Rucker James J. H.ORCID, Sachdev Perminder S.ORCID, Sando Sigrid B., Schofield Peter R.ORCID, Schork Andrew J.ORCID, Schumann GunterORCID, Shin JeanORCID, Shumskaya Elena, Silva Ana I.ORCID, Sisodiya Sanjay M., Steen Vidar M., Stein Dan J.ORCID, Strike Lachlan T.ORCID, Suzuki Ikuo K., Tamnes Christian K.ORCID, Teumer AlexanderORCID, Thalamuthu Anbupalam, Tordesillas-Gutiérrez DianaORCID, Uhlmann Anne, Ulfarsson Magnus O.ORCID, van ‘t Ent Dennis, van den Bree Marianne B. M.ORCID, Vanderhaeghen PierreORCID, Vassos EvangelosORCID, Wen WeiORCID, Wittfeld KatharinaORCID, Wright Margaret J.ORCID, Agartz Ingrid, Djurovic SrdjanORCID, Westlye Lars T.ORCID, Stefansson HreinnORCID, Stefansson KariORCID, Jacquemont SébastienORCID, Thompson Paul M., Andreassen Ole A.ORCID
Abstract
AbstractLow-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.
Publisher
Springer Science and Business Media LLC
Subject
Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health
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