1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
Authors: Sønderby Ida E. , van der Meer Dennis , Moreau Clara , Kaufmann Tobias , Walters G. Bragi , Ellegaard Maria , Abdellaoui Abdel , Ames David , Amunts Katrin , Andersson Micael , Armstrong Nicola J. , Bernard Manon , Blackburn Nicholas B. , Blangero John , Boomsma Dorret I. , Brodaty Henry , Brouwer Rachel M. , Bülow Robin , Bøen Rune , Cahn Wiepke , Calhoun Vince D. , Caspers Svenja , Ching Christopher R. K. , Cichon Sven , Ciufolini Simone , Crespo-Facorro Benedicto , Curran Joanne E. , Dale Anders M. , Dalvie Shareefa , Dazzan Paola , de Geus Eco J. C. , de Zubicaray Greig I. , de Zwarte Sonja M. C. , Desrivieres Sylvane , Doherty Joanne L. , Donohoe Gary , Draganski Bogdan , Ehrlich Stefan , Eising Else , Espeseth Thomas , Fejgin Kim , Fisher Simon E. , Fladby Tormod , Frei Oleksandr , Frouin Vincent , Fukunaga Masaki , Gareau Thomas , Ge Tian , Glahn David C. , Grabe Hans J. , Groenewold Nynke A. , Gústafsson Ómar , Haavik Jan , Haberg Asta K. , Hall Jeremy , Hashimoto Ryota , Hehir-Kwa Jayne Y. , Hibar Derrek P. , Hillegers Manon H. J. , Hoffmann Per , Holleran Laurena , Holmes Avram J. , Homuth Georg , Hottenga Jouke-Jan , Hulshoff Pol Hilleke E. , Ikeda Masashi , Jahanshad Neda , Jockwitz Christiane , Johansson Stefan , Jönsson Erik G. , Jørgensen Niklas R. , Kikuchi Masataka , Knowles Emma E. M. , Kumar Kuldeep , Le Hellard Stephanie , Leu Costin , Linden David E. J. , Liu Jingyu , Lundervold Arvid , Lundervold Astri Johansen , Maillard Anne M. , Martin Nicholas G. , Martin-Brevet Sandra , Mather Karen A. , Mathias Samuel R. , McMahon Katie L. , McRae Allan F. , Medland Sarah E. , Meyer-Lindenberg Andreas , Moberget Torgeir , Modenato Claudia , Sánchez Jennifer Monereo , Morris Derek W. , Mühleisen Thomas W. , Murray Robin M. , Nielsen Jacob , Nordvik Jan E. , Nyberg Lars , Loohuis Loes M. Olde , Ophoff Roel A. , Owen Michael J. , Paus Tomas , Pausova Zdenka , Peralta Juan M. , Pike G. Bruce , Prieto Carlos , Quinlan Erin B. , Reinbold Céline S. , Marques Tiago Reis , Rucker James J. H. , Sachdev Perminder S. , Sando Sigrid B. , Schofield Peter R. , Schork Andrew J. , Schumann Gunter , Shin Jean , Shumskaya Elena , Silva Ana I. , Sisodiya Sanjay M. , Steen Vidar M. , Stein Dan J. , Strike Lachlan T. , Suzuki Ikuo K. , Tamnes Christian K. , Teumer Alexander , Thalamuthu Anbupalam , Tordesillas-Gutiérrez Diana , Uhlmann Anne , Ulfarsson Magnus O. , van ‘t Ent Dennis , van den Bree Marianne B. M. , Vanderhaeghen Pierre , Vassos Evangelos , Wen Wei , Wittfeld Katharina , Wright Margaret J. , Agartz Ingrid , Djurovic Srdjan , Westlye Lars T. , Stefansson Hreinn , Stefansson Kari , Jacquemont Sébastien , Thompson Paul M. , Andreassen Ole A. ,   for the ENIGMA-CNV working group, van der Meer Dennis , de Geus Eco J. C. , de Zubicaray Greig I. , de Zwarte Sonja M. C. , Le Hellard Stephanie , van ‘t Ent Dennis , van den Bree Marianne B. M. 
Published: March 2021

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.