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

Ida E. Sønderby; Dorret I. Boomsma; Rachel M. Brouwer; Eco J.C. de Geus; Jouke Jan Hottenga; Dennis van 't Ent; Ole A. Andreassen; ENIGMA-CNV working group

doi:10.1038/s41398-021-01213-0

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

Ida E. Sønderby, Dorret I. Boomsma, Rachel M. Brouwer, Eco J.C. de Geus, Jouke Jan Hottenga, Dennis van 't Ent, Ole A. Andreassen, ENIGMA-CNV working group

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	182
Pages (from-to)	182
Number of pages	1
Journal	Translational Psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01213-0 https://doi.org/10.1038/s41398-021-01213-0
Publication status	Published - 22 Mar 2021

Bibliographical note

Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

Funding

H.B. is an advisory board member for Nutricia Australia. He has received research funding from the EU ‘Joint Programme Neurodegenerative Disorders’ (JPND) and the National Health and Medical Research Council, Australia. H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Servier, Neuraxpharm and Janssen Cilag. He has received research funding from the German Research Foundation (DFG), the German Ministry of Education and Research (BMBF), the DAMP Foundation, Fresenius Medical Care, the EU ‘Joint Programme Neurodegenerative Disorders’ (JPND) and the European Social Fund (ESF). C.R.K.C., P.M.T. and N.J. received partial grant support from Biogen Inc. (Boston), for research unrelated to the topic of this manuscript. B.C.-F. has received honoraria from Janssen Cilag, Otsuka and Lundbeck for educational and advisory/consultant activities unrelated with the present research. A.M.D. is a Founder of and holds equity in CorTechs Labs Inc., and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity Inc., and receives funding through a research agreement with General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. G.B.W., O.G., M.O.U., H.S. and K.S. are employees of deCODE genetics (Amgen). D.P.H. is an employee of Genentech Inc. O.A.A. has received speakers honorarium from Lundbeck, and is a consultant to HealthLytix. A.J.L. has received speaker’s honorarium from Shire. M.J.O., J.H. and v.d.B. report grants from Takeda Pharmaceuticals outside of the submitted work. D.J.S. has received research grants and/or consultancy honoraria from Lundbeck and Sun. D.E.J.L. receives book royalties from Springer Nature and Oxford University Press. T.F. is on the Novo Nordisk advisory board. P.S.S. is on the Expert Advisory Committee of Biogen Australia. All other authors declare no competing financial interests. Osaka: Osaka study was supported by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS: Grant Number JP18dm0207006), Brain/MINDS& beyond studies (Grant Number JP20dm0307002) and Health and Labour Sciences Research Grants for Comprehensive Research on Persons with Disabilities (Grant Number JP20dk0307081) from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (KAKENHI; Grant Numbers JP25293250 and JP16H05375). Some computations were performed at the Research Center for Computational Science, Okazaki, Japan. PAFIP: The PAFIP study was supported by Instituto de Salud Carlos III, FIS 00/ 3095, 01/3129, PI020499, PI060507, PI10/00183, the SENY Fundació Research Grant CI2005-0308007 and the FundaciónMarqués de Valdecilla API07/011. Biological samples from our cohort were stored at the Valdecilla Biobank and genotyping services were conducted at the Spanish ‘Centro Nacional de Genotipado’ (CEGEN-ISCIII). MCIC/COBRE: The study is funded by the National Institutes of Health studies R01EB006841, P20GM103472 and P30GM122734 and Department of Energy DE-FG02-99ER62764. PING: Data collection and sharing for the Paediatric Imaging, Neurocognition and Genetics (PING) Study (National Institutes of Health Grant RC2DA029475) were funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. A full list of PING investigators is at http://pingstudy.ucsd.edu/investigators.html. QTIM: The QTIM study was supported by the National Institute of Child Health and Human Development (R01 HD050735) and the National Health and Medical Research Council (NHMRC 486682, 1009064), Australia. Genotyping was supported by NHMRC (389875). Medland is supported in part by an NHMRC fellowship (APP1103623). SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide single-nucleotide polymorphism typing in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. StrokeMRI: StrokeMRI was supported by the Norwegian ExtraFoundation for Health and Rehabilitation(2015/FO5146), the Research Council of Norway (249795, 262372), the South-Eastern Norway Regional Health Authority (2014097, 2015044, 2015073) and the Department of Psychology, University of Oslo. Sydney MAS: The Sydney Memory and Aging Study (Sydney MAS) is funded by National and HealthMedical Research Council (NHMRC) Programme and Project Grants (ID350833, ID568969 and ID109308). We also thank the Sydney MAS participants and the Research Team. SYS: The SYS Study is supported by Canadian Institutes of Health Research. TOP: Centre of Excellence: RCN #23273 and RCN #226971. Part of this work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) ([email protected]). The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement no. 609020—Scientia Fellows; the Research Council of Norway (RCN) #276082—A lifespan perspective on mental illness: toward precision medicine using multimodal brain imaging and genetics. Ida E. Sønderby and Rune Bøen are supported by South-Eastern Norway Regional Health Authority (#2020060). Ida E. Sønderby and Ole A. Andreassen have received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement no. 847776 (CoMorMent project) and the KG Jebsen Foundation (SKGJ-MED-021). UCLA_UMCU: The UCLA_UMCU cohort comprises of six studies which were supported by National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) (20244 to Prof. Hillegers), The Netherlands Organisation for Health Research and Development (ZonMw) (908-02-123 to Prof. Hulshoff Pol), and Netherlands Organisation for Scientific Research (NWO 9120818 and NWO-VIDI 917-46-370 to Prof. Hulshoff Pol). The GROUP study was funded through the Geestkracht programme of the Dutch Health Research Council (ZonMw, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly and Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ inGeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord-Holland-Noord. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia Psycho-medical Center, The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh, voor Geestelijke Gezondheid, Mondriaan, Virenzeriagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-JozefKortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Center Utrecht and the mental health institutions: Altrecht, GGZ Centraal and Delta.). UK Biobank: This work made use of data sharing from UK Biobank (under project code 27412). Others: Work by Pierre Vanderhaeghen was funded by Grants of the European Research Council (ERC Adv Grant GENDEVOCORTEX), the EOS Programme, the Belgian FWO, the AXA Research Fund and the Belgian Queen Elizabeth Foundation. Ikuo K. Suzuki was supported by a postdoctoral fellowship of the FRS/FNRS.

Funders	Funder number
Belgian Queen Elizabeth Foundation
Department of Psychology, University of Oslo
Dutch Health Research Council	10-000-1001
FRS
Federal State of Mecklenburg-West Pomerania
Ministry of Cultural Affairs
National Alliance for Research in Schizophrenia and Affective Disorders	20244
Norwegian ExtraFoundation for Health and Rehabilitation	2015/FO5146
SENY	CI2005-0308007
National Institutes of Health	P30GM122734, R01EB006841, P20GM103472
U.S. Department of Energy	DE-FG02-99ER62764, RC2DA029475
National Institute on Drug Abuse
National Institute of Child Health and Human Development	R01 HD050735
Biogen
Stiftelsen Kristian Gerhard Jebsen	SKGJ-MED-021
Japan Agency for Medical Research and Development	JP25293250, JP16H05375
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Horizon 2020 Framework Programme
Seventh Framework Programme	602768, 268800, 695313, 286213, 602805, 609020, 643051, 230374, 602450, 945539, 278948, 771057, 284167, 603016, 847776
FP7 People: Marie-Curie Actions	276082
EU Joint Programme – Neurodegenerative Disease Research
Fresenius Medical Care North America
European Resuscitation Council
Canadian Institutes of Health Research
European Commission
European Research Council
National Health and Medical Research Council	ID568969, APP1103623, ID350833, 486682, 389875, ID109308, 1009064
Deutsche Forschungsgemeinschaft
ZonMw	908-02-123
AXA Research Fund
Bundesministerium für Bildung und Forschung	01ZZ0403, 01ZZ0103, 01ZZ9603
Fonds De La Recherche Scientifique - FNRS
Fonds Wetenschappelijk Onderzoek
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	NWO-VIDI 917-46-370, 9120818
Instituto de Salud Carlos III	FIS 00/ 3095, 01/3129, PI060507, PI020499, PI10/00183
European Social Fund
Seventh Framework Programme
Norges forskningsråd	262372, 249795
Helse Sør-Øst RHF	2015073, 2015044, 2014097
Damp Stiftung
Fundación Marqués de Valdecilla	API07/011

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sønderby, I. E., Boomsma, D. I., Brouwer, R. M., de Geus, E. J. C., Hottenga, J. J., van 't Ent, D., Andreassen, O. A., & ENIGMA-CNV working group (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry, 11(1), 182. Article 182. https://doi.org/10.1038/s41398-021-01213-0, https://doi.org/10.1038/s41398-021-01213-0

@article{d0641ece9e6b41f7bfe843993628acdd,

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

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.",

author = "S{\o}nderby, {Ida E.} and {van der Meer}, Dennis and Clara Moreau and Tobias Kaufmann and Walters, {G. Bragi} and Maria Ellegaard and Abdel Abdellaoui and David Ames and Katrin Amunts and Micael Andersson and Armstrong, {Nicola J.} and Manon Bernard and Blackburn, {Nicholas B.} and John Blangero and Boomsma, {Dorret I.} and Henry Brodaty and Brouwer, {Rachel M.} and Robin B{\"u}low and Rune B{\o}en and Wiepke Cahn and Calhoun, {Vince D.} and Svenja Caspers and Ching, {Christopher R.K.} and Sven Cichon and Simone Ciufolini and Benedicto Crespo-Facorro and Curran, {Joanne E.} and Dale, {Anders M.} and Shareefa Dalvie and Paola Dazzan and {de Geus}, {Eco J.C.} and {de Zubicaray}, {Greig I.} and {de Zwarte}, {Sonja M.C.} and Sylvane Desrivieres and Doherty, {Joanne L.} and Gary Donohoe and Bogdan Draganski and Stefan Ehrlich and Else Eising and Thomas Espeseth and Kim Fejgin and Fisher, {Simon E.} and Tormod Fladby and Oleksandr Frei and Vincent Frouin and Masaki Fukunaga and Thomas Gareau and Tian Ge and Glahn, {David C.} and Grabe, {Hans J.} and Groenewold, {Nynke A.} and {\'O}mar G{\'u}stafsson and Jan Haavik and Haberg, {Asta K.} and Jeremy Hall and Ryota Hashimoto and Hehir-Kwa, {Jayne Y.} and Hibar, {Derrek P.} and Hillegers, {Manon H.J.} and Per Hoffmann and Laurena Holleran and Holmes, {Avram J.} and Georg Homuth and Hottenga, {Jouke Jan} and {Hulshoff Pol}, {Hilleke E.} and Masashi Ikeda and Neda Jahanshad and Christiane Jockwitz and Stefan Johansson and J{\"o}nsson, {Erik G.} and J{\o}rgensen, {Niklas R.} and Masataka Kikuchi and Knowles, {Emma E.M.} and Kuldeep Kumar and {Le Hellard}, Stephanie and Costin Leu and Linden, {David E.J.} and Jingyu Liu and Arvid Lundervold and Lundervold, {Astri Johansen} and Maillard, {Anne M.} and Martin, {Nicholas G.} and Sandra Martin-Brevet and Mather, {Karen A.} and Mathias, {Samuel R.} and McMahon, {Katie L.} and McRae, {Allan F.} and Medland, {Sarah E.} and Andreas Meyer-Lindenberg and Torgeir Moberget and Claudia Modenato and S{\'a}nchez, {Jennifer Monereo} and Morris, {Derek W.} and M{\"u}hleisen, {Thomas W.} and Murray, {Robin M.} and Jacob Nielsen and Nordvik, {Jan E.} and Lars Nyberg and Loohuis, {Loes M.Olde} and Ophoff, {Roel A.} and Owen, {Michael J.} and Tomas Paus and Zdenka Pausova and Peralta, {Juan M.} and Pike, {G. Bruce} and Carlos Prieto and Quinlan, {Erin B.} and Reinbold, {C{\'e}line S.} and Marques, {Tiago Reis} and Rucker, {James J.H.} and Sachdev, {Perminder S.} and Sando, {Sigrid B.} and Schofield, {Peter R.} and Schork, {Andrew J.} and Gunter Schumann and Jean Shin and Elena Shumskaya and Silva, {Ana I.} and Sisodiya, {Sanjay M.} and Steen, {Vidar M.} and Stein, {Dan J.} and Strike, {Lachlan T.} and Suzuki, {Ikuo K.} and Tamnes, {Christian K.} and Alexander Teumer and Anbupalam Thalamuthu and Diana Tordesillas-Guti{\'e}rrez and Anne Uhlmann and Ulfarsson, {Magnus O.} and {van 't Ent}, Dennis and {van den Bree}, {Marianne B.M.} and Pierre Vanderhaeghen and Evangelos Vassos and Wei Wen and Katharina Wittfeld and Wright, {Margaret J.} and Ingrid Agartz and Srdjan Djurovic and Westlye, {Lars T.} and Hreinn Stefansson and Kari Stefansson and S{\'e}bastien Jacquemont and Thompson, {Paul M.} and Andreassen, {Ole A.} and {ENIGMA-CNV working group}",

note = "Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",

year = "2021",

month = mar,

day = "22",

doi = "10.1038/s41398-021-01213-0",

language = "English",

volume = "11",

pages = "182",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Sønderby, IE, Boomsma, DI , Brouwer, RM , de Geus, EJC , Hottenga, JJ , van 't Ent, D, Andreassen, OA & ENIGMA-CNV working group 2021, '1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans', Translational Psychiatry, vol. 11, no. 1, 182, pp. 182. https://doi.org/10.1038/s41398-021-01213-0, https://doi.org/10.1038/s41398-021-01213-0

TY - JOUR

T1 - 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

AU - Sønderby, Ida E.

AU - van der Meer, Dennis

AU - Moreau, Clara

AU - Kaufmann, Tobias

AU - Walters, G. Bragi

AU - Ellegaard, Maria

AU - Abdellaoui, Abdel

AU - Ames, David

AU - Amunts, Katrin

AU - Andersson, Micael

AU - Armstrong, Nicola J.

AU - Bernard, Manon

AU - Blackburn, Nicholas B.

AU - Blangero, John

AU - Boomsma, Dorret I.

AU - Brodaty, Henry

AU - Brouwer, Rachel M.

AU - Bülow, Robin

AU - Bøen, Rune

AU - Cahn, Wiepke

AU - Calhoun, Vince D.

AU - Caspers, Svenja

AU - Ching, Christopher R.K.

AU - Cichon, Sven

AU - Ciufolini, Simone

AU - Crespo-Facorro, Benedicto

AU - Curran, Joanne E.

AU - Dale, Anders M.

AU - Dalvie, Shareefa

AU - Dazzan, Paola

AU - de Geus, Eco J.C.

AU - de Zubicaray, Greig I.

AU - de Zwarte, Sonja M.C.

AU - Desrivieres, Sylvane

AU - Doherty, Joanne L.

AU - Donohoe, Gary

AU - Draganski, Bogdan

AU - Ehrlich, Stefan

AU - Eising, Else

AU - Espeseth, Thomas

AU - Fejgin, Kim

AU - Fisher, Simon E.

AU - Fladby, Tormod

AU - Frei, Oleksandr

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Gareau, Thomas

AU - Ge, Tian

AU - Glahn, David C.

AU - Grabe, Hans J.

AU - Groenewold, Nynke A.

AU - Gústafsson, Ómar

AU - Haavik, Jan

AU - Haberg, Asta K.

AU - Hall, Jeremy

AU - Hashimoto, Ryota

AU - Hehir-Kwa, Jayne Y.

AU - Hibar, Derrek P.

AU - Hillegers, Manon H.J.

AU - Hoffmann, Per

AU - Holleran, Laurena

AU - Holmes, Avram J.

AU - Homuth, Georg

AU - Hottenga, Jouke Jan

AU - Hulshoff Pol, Hilleke E.

AU - Ikeda, Masashi

AU - Jahanshad, Neda

AU - Jockwitz, Christiane

AU - Johansson, Stefan

AU - Jönsson, Erik G.

AU - Jørgensen, Niklas R.

AU - Kikuchi, Masataka

AU - Knowles, Emma E.M.

AU - Kumar, Kuldeep

AU - Le Hellard, Stephanie

AU - Leu, Costin

AU - Linden, David E.J.

AU - Liu, Jingyu

AU - Lundervold, Arvid

AU - Lundervold, Astri Johansen

AU - Maillard, Anne M.

AU - Martin, Nicholas G.

AU - Martin-Brevet, Sandra

AU - Mather, Karen A.

AU - Mathias, Samuel R.

AU - McMahon, Katie L.

AU - McRae, Allan F.

AU - Medland, Sarah E.

AU - Meyer-Lindenberg, Andreas

AU - Moberget, Torgeir

AU - Modenato, Claudia

AU - Sánchez, Jennifer Monereo

AU - Morris, Derek W.

AU - Mühleisen, Thomas W.

AU - Murray, Robin M.

AU - Nielsen, Jacob

AU - Nordvik, Jan E.

AU - Nyberg, Lars

AU - Loohuis, Loes M.Olde

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Peralta, Juan M.

AU - Pike, G. Bruce

AU - Prieto, Carlos

AU - Quinlan, Erin B.

AU - Reinbold, Céline S.

AU - Marques, Tiago Reis

AU - Rucker, James J.H.

AU - Sachdev, Perminder S.

AU - Sando, Sigrid B.

AU - Schofield, Peter R.

AU - Schork, Andrew J.

AU - Schumann, Gunter

AU - Shin, Jean

AU - Shumskaya, Elena

AU - Silva, Ana I.

AU - Sisodiya, Sanjay M.

AU - Steen, Vidar M.

AU - Stein, Dan J.

AU - Strike, Lachlan T.

AU - Suzuki, Ikuo K.

AU - Tamnes, Christian K.

AU - Teumer, Alexander

AU - Thalamuthu, Anbupalam

AU - Tordesillas-Gutiérrez, Diana

AU - Uhlmann, Anne

AU - Ulfarsson, Magnus O.

AU - van 't Ent, Dennis

AU - van den Bree, Marianne B.M.

AU - Vanderhaeghen, Pierre

AU - Vassos, Evangelos

AU - Wen, Wei

AU - Wittfeld, Katharina

AU - Wright, Margaret J.

AU - Agartz, Ingrid

AU - Djurovic, Srdjan

AU - Westlye, Lars T.

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Jacquemont, Sébastien

AU - Thompson, Paul M.

AU - Andreassen, Ole A.

AU - ENIGMA-CNV working group

N1 - Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

PY - 2021/3/22

Y1 - 2021/3/22

N2 - 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.

AB - 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.

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U2 - 10.1038/s41398-021-01213-0

DO - 10.1038/s41398-021-01213-0

M3 - Article

C2 - 33753722

SN - 2158-3188

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SP - 182

JO - Translational Psychiatry

JF - Translational Psychiatry

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ER -

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

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