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

for the 16p11.2 European Consortium, for the ENIGMA-CNV working group

doi:10.1038/s41380-018-0118-1

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

for the 16p11.2 European Consortium, for the ENIGMA-CNV working group

University of Oslo
deCODE Genetics
University of Southern California
Johnson & Johnson
University of Lausanne
Vrije Universiteit Amsterdam
Amsterdam University Medical Centers
National Ageing Research Institute
University of Melbourne
Jülich Research Centre
Heinrich Heine University Düsseldorf
JARA-BRAIN
Umeå University
Murdoch University
University of Toronto
University of Texas Rio Grande Valley
Radboud University Nijmegen
University of Bergen
University of New South Wales
Utrecht University
University of Greifswald
University of New Mexico
Royal College of Surgeons in Ireland
University of California at San Diego
University of Basel
King's College London
Trinity College Dublin
Hospital Universitario Marques de Valdecilla
San Juan de Dios Sanitary Park
Department of Psychiatry and Mental Health
South London and Maudsley NHS Foundation Trust
VU University Medical Center
Queensland University of Technology
University of California at Davis
University of Galway
Max Planck Institute for Human Cognitive and Brain Sciences
Technische Universität Dresden
Massachusetts General Hospital
Max Planck Institute for Psycholinguistics
Commissariat à l’énergie atomique et aux énergies alternatives
National Institutes of Natural Sciences - National Institute for Physiological Sciences
Yale University
Institute of Living
Norwegian University of Science and Technology
The University of Osaka
Princess Máxima Center for Pediatric Oncology
Humboldt University of Berlin
Erasmus University Rotterdam
University of Bonn
Fujita Health University
RWTH Aachen University
Karolinska Institutet
Sunnaas Rehabilitation Hospital HT
The University of Sydney
Cleveland Clinic Foundation
University College London
The Mind Research Network
Queensland Institute of Medical Research
University of Queensland
Amsterdam UMC
University of Montreal
University of California at Los Angeles
Child Mind Institute, Inc.
University of Calgary
Universidad de Salamanca
Hammersmith Hospital
ORYGEN Youth Health
Neuroscience Research Australia
Chalfont Centre for Epilepsy
University of Cape Town
Risk and Resilience in Mental Disorders Research Unit
Valdecilla Biomedical Research Institute IDIVAL
Georgia State University
Stellenbosch University
University of Iceland
Medical Research Council
German Center for Neurodegenerative Diseases
University of Montreal

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

Abstract

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 × 10⁻⁶, 1.7 × 10⁻ ⁹, 3.5 × 10⁻¹² and 1.0 × 10⁻⁴, 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.

Original language	English
Pages (from-to)	584-602
Number of pages	19
Journal	Molecular Psychiatry
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/s41380-018-0118-1
Publication status	Published - 1 Mar 2020
Externally published	Yes

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10.1038/s41380-018-0118-1

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

abstract = "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 × 10−6, 1.7 × 10− 9, 3.5 × 10−12 and 1.0 × 10−4, 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.",

author = "\{for the 16p11.2 European Consortium, for the ENIGMA-CNV working group\} and S{\o}nderby, \{Ida E.\} and {\'O}mar G{\'u}stafsson and Doan, \{Nhat Trung\} and Hibar, \{Derrek P.\} and Sandra Martin-Brevet and Abdel Abdellaoui and David Ames and Katrin Amunts and Michael Andersson and Armstrong, \{Nicola J.\} and Manon Bernard and Nicholas Blackburn and John Blangero and Boomsma, \{Dorret I.\} and Janita Bralten and Brattbak, \{Hans Richard\} and Henry Brodaty and Brouwer, \{Rachel M.\} and Robin B{\"u}low and Vince Calhoun and Svenja Caspers and Gianpiero Cavalleri and Chen, \{Chi Hua\} and Sven Cichon and Simone Ciufolini and Aiden Corvin 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 Norman Delanty and \{den Braber\}, Anouk and Sylvane Desrivi{\`e}res and Gary Donohoe and Bogdan Draganski and Stefan Ehrlich and Thomas Espeseth and Fisher, \{Simon E.\} and Barbara Franke and Vincent Frouin and Masaki Fukunaga and Thomas Gareau and Glahn, \{David C.\} and Hans Grabe and Groenewold, \{Nynke A.\} and Hottenga, \{Jouke Jan\}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2020",

month = mar,

day = "1",

doi = "10.1038/s41380-018-0118-1",

language = "English",

volume = "25",

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journal = "Molecular Psychiatry",

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T1 - Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

AU - for the 16p11.2 European Consortium, for the ENIGMA-CNV working group

AU - Sønderby, Ida E.

AU - Gústafsson, Ómar

AU - Doan, Nhat Trung

AU - Hibar, Derrek P.

AU - Martin-Brevet, Sandra

AU - Abdellaoui, Abdel

AU - Ames, David

AU - Amunts, Katrin

AU - Andersson, Michael

AU - Armstrong, Nicola J.

AU - Bernard, Manon

AU - Blackburn, Nicholas

AU - Blangero, John

AU - Boomsma, Dorret I.

AU - Bralten, Janita

AU - Brattbak, Hans Richard

AU - Brodaty, Henry

AU - Brouwer, Rachel M.

AU - Bülow, Robin

AU - Calhoun, Vince

AU - Caspers, Svenja

AU - Cavalleri, Gianpiero

AU - Chen, Chi Hua

AU - Cichon, Sven

AU - Ciufolini, Simone

AU - Corvin, Aiden

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 - Delanty, Norman

AU - den Braber, Anouk

AU - Desrivières, Sylvane

AU - Donohoe, Gary

AU - Draganski, Bogdan

AU - Ehrlich, Stefan

AU - Espeseth, Thomas

AU - Fisher, Simon E.

AU - Franke, Barbara

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Gareau, Thomas

AU - Glahn, David C.

AU - Grabe, Hans

AU - Groenewold, Nynke A.

AU - Hottenga, Jouke Jan

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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 × 10−6, 1.7 × 10− 9, 3.5 × 10−12 and 1.0 × 10−4, 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.

AB - 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 × 10−6, 1.7 × 10− 9, 3.5 × 10−12 and 1.0 × 10−4, 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.

UR - https://www.scopus.com/pages/publications/85054383956

U2 - 10.1038/s41380-018-0118-1

DO - 10.1038/s41380-018-0118-1

M3 - Article

C2 - 30283035

AN - SCOPUS:85054383956

SN - 1359-4184

VL - 25

SP - 584

EP - 602

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 3

ER -

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

Abstract

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