Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology

ENIGMA-CNV Working Group

doi:10.1016/j.bpsc.2025.05.010

Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology

ENIGMA-CNV Working Group

Maastricht University
Cardiff University
University of Minnesota Twin Cities
University of Oslo
Karolinska Institutet
Diakonhjemmet Hospital
University of Melbourne
Curtin University
Centre Borelli
Établissement Public de Santé Barthélémy Durand
Heidelberg University
University of Toronto
UHN - Toronto General Hospital
University of California at Los Angeles
University of Texas Rio Grande Valley
Vrije Universiteit Amsterdam
Amsterdam UMC
University of Greifswald
Emory University
University of Newcastle
King's College London
National Female Hormone Clinic
Centro de Investigación Biomèdica en Red de Salud Mental (CIBERSAM)
Hospital Universitario Virgen del Rocio
South African Medical Research Council
University of Cape Town
Queensland University of Technology
University of Galway
Public Health Wales
Oslo New University College
Université Paris-Saclay
University of Vermont
Boston Children's Hospital
Harvard University
University of Utah
University of Nottingham
Roehampton University
Illinois Institute of Technology
University of Bergen
Norwegian University of Science and Technology
Charité – Universitätsmedizin Berlin
Partner Site Berlin
University of Hamburg
Hamad bin Khalifa University
University of Montreal
University of Southern California
University of Groningen
Université de Bordeaux
Georgia State University
University of New South Wales
Neuroscience Research Australia
University of Pennsylvania
Center for Applied Genomics
University of Rome La Sapienza
University of Queensland
Queensland Institute of Medical Research
Royal College of Surgeons in Ireland
University Medical Center Schleswig-Holstein
Sorbonne Université
McGill University
University of Göttingen
Imperial College Healthcare NHS Trust
Prince of Wales Hospital
Fudan University
German Centre for Cardiovascular Research
Instituto de Física de Cantabria
Hospital Universitario Marques de Valdecilla
Technische Universität Dresden
Charles R. Drew University of Medicine and Science
Universidad de Cantabria

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Abstract

Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

Original language	English
Pages (from-to)	1093-1106
Number of pages	14
Journal	Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume	10
Issue number	10
DOIs	https://doi.org/10.1016/j.bpsc.2025.05.010
Publication status	Published - Oct 2025

Keywords

Autism
Neuroimaging
Psychiatric disorders
Schizophrenia
Structural imaging

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@article{9a13afae4af144f99ad3494b0acd498a,

title = "Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology",

abstract = "Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54\% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.",

keywords = "Autism, Neuroimaging, Psychiatric disorders, Schizophrenia, Structural imaging",

author = "\{ENIGMA-CNV Working Group\} and Silva, \{Ana I.\} and S{\o}nderby, \{Ida E.\} and George Kirov and Abdel Abdellaoui and Ingrid Agartz and David Ames and Armstrong, \{Nicola J.\} and Eric Artiges and Tobias Banaschewski and Bassett, \{Anne S.\} and Bearden, \{Carrie E.\} and John Blangero and Rune Boen and Boomsma, \{Dorret I.\} and Robin B{\"u}low and Butcher, \{Nancy J.\} and Vince Calhoun and Campbell, \{Linda E.\} and Chow, \{Eva W.C.\} and Simone Ciufolini and Craig, \{Michael C.\} and Benedicto Crespo-Farroco and Cunningham, \{Adam C.\} and Shareefa Dalvie and Eileen Daly and Paola Dazzan and \{de Geus\}, \{Eco J.C.\} and \{de Zubicaray\}, \{Greig I.\} and Doherty, \{Joanne L.\} and Gary Donohoe and Mark Drakesmith and Thomas Espeseth and Vincent Frouin and Hugh Garavan and Glahn, \{David C.\} and Goodrich-Hunsaker, \{Naomi J.\} and Gowland, \{Penny A.\} and Grabe, \{Hans J.\} and Antoine Grigis and Maria Gudbrandsen and Gutman, \{Boris A.\} and Jan Haavik and H{\aa}berg, \{Asta K.\} and Jeremy Hall and Andreas Heinz and Sarah Hohmann and Hottenga, \{Jouke Jan\} and S{\'e}bastien Jacquemont and Neda Jahanshad and Jonas, \{Rachel K.\} and Jones, \{Derek K.\} and J{\"o}nsson, \{Erik G.\} and Sanne Koops and Kuldeep Kumar and \{Le Hellard\}, Stephanie and Herve Lemaitre and Jingyu Liu and Lundervold, \{Astri J.\} and Martinot, \{Jean Luc\} and Mather, \{Karen A.\} and McDonald-McGinn, \{Donna M.\} and McMahon, \{Katie L.\} and McRae, \{Allan F.\} and Medland, \{Sarah E.\} and Moreau, \{Clara A.\} and Murphy, \{Kieran C.\} and Declan Murphy and Murray, \{Robin M.\} and Frauke Nees and Owen, \{Michael J.\} and \{Paill{\`e}re Martinot\}, \{Marie Laure\} and Orfanos, \{Diimitri Papadopoulos\} and Tomas Paus and Luise Poustka and Marques, \{Tiago Reis\} and Roalf, \{David R.\} and Sachdev, \{Perminder S.\} and Freda Scheffler and Schmitt, \{J. Eric\} and Gunter Schumann and Steen, \{Vidar M.\} and Stein, \{Dan J.\} and Strike, \{Lachlan T.\} and Alexander Teumer and Anbupalam Thalamuthu and Thomopoulos, \{Sophia I.\} and Diana Tordesillas-Guti{\'e}rrez and Trollor, \{Julian N.\} and Anne Uhlmann and Ariana Vajdi and \{van {\textquoteright}t Ent\}, Dennis and \{van Amelsvoort\}, Therese and \{van den Bree\}, \{Marianne B.M.\} and \{van der Meer\}, Dennis and Javier V{\'a}zquez-Bourgon and Villal{\'o}n-Reina, \{Julio E.\} and Uwe V{\"o}lker and Henry V{\"o}lzke and Vorstman, \{Jacob A.S.\} and Westlye, \{Lars T.\} and Nigel Williams and Katharina Wittfeld and Wright, \{Margaret J.\} and Thompson, \{Paul M.\} and Andreassen, \{Ole A.\} and Linden, \{David E.J.\}",

note = "Publisher Copyright: {\textcopyright} 2025 Society of Biological Psychiatry. Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/",

year = "2025",

month = oct,

doi = "10.1016/j.bpsc.2025.05.010",

language = "English",

volume = "10",

pages = "1093--1106",

journal = "Biological Psychiatry: Cognitive Neuroscience and Neuroimaging",

issn = "2451-9022",

publisher = "Elsevier Inc.",

number = "10",

}

TY - JOUR

T1 - Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology

AU - ENIGMA-CNV Working Group

AU - Silva, Ana I.

AU - Sønderby, Ida E.

AU - Kirov, George

AU - Abdellaoui, Abdel

AU - Agartz, Ingrid

AU - Ames, David

AU - Armstrong, Nicola J.

AU - Artiges, Eric

AU - Banaschewski, Tobias

AU - Bassett, Anne S.

AU - Bearden, Carrie E.

AU - Blangero, John

AU - Boen, Rune

AU - Boomsma, Dorret I.

AU - Bülow, Robin

AU - Butcher, Nancy J.

AU - Calhoun, Vince

AU - Campbell, Linda E.

AU - Chow, Eva W.C.

AU - Ciufolini, Simone

AU - Craig, Michael C.

AU - Crespo-Farroco, Benedicto

AU - Cunningham, Adam C.

AU - Dalvie, Shareefa

AU - Daly, Eileen

AU - Dazzan, Paola

AU - de Geus, Eco J.C.

AU - de Zubicaray, Greig I.

AU - Doherty, Joanne L.

AU - Donohoe, Gary

AU - Drakesmith, Mark

AU - Espeseth, Thomas

AU - Frouin, Vincent

AU - Garavan, Hugh

AU - Glahn, David C.

AU - Goodrich-Hunsaker, Naomi J.

AU - Gowland, Penny A.

AU - Grabe, Hans J.

AU - Grigis, Antoine

AU - Gudbrandsen, Maria

AU - Gutman, Boris A.

AU - Haavik, Jan

AU - Håberg, Asta K.

AU - Hall, Jeremy

AU - Heinz, Andreas

AU - Hohmann, Sarah

AU - Hottenga, Jouke Jan

AU - Jacquemont, Sébastien

AU - Jahanshad, Neda

AU - Jonas, Rachel K.

AU - Jones, Derek K.

AU - Jönsson, Erik G.

AU - Koops, Sanne

AU - Kumar, Kuldeep

AU - Le Hellard, Stephanie

AU - Lemaitre, Herve

AU - Liu, Jingyu

AU - Lundervold, Astri J.

AU - Martinot, Jean Luc

AU - Mather, Karen A.

AU - McDonald-McGinn, Donna M.

AU - McMahon, Katie L.

AU - McRae, Allan F.

AU - Medland, Sarah E.

AU - Moreau, Clara A.

AU - Murphy, Kieran C.

AU - Murphy, Declan

AU - Murray, Robin M.

AU - Nees, Frauke

AU - Owen, Michael J.

AU - Paillère Martinot, Marie Laure

AU - Orfanos, Diimitri Papadopoulos

AU - Paus, Tomas

AU - Poustka, Luise

AU - Marques, Tiago Reis

AU - Roalf, David R.

AU - Sachdev, Perminder S.

AU - Scheffler, Freda

AU - Schmitt, J. Eric

AU - Schumann, Gunter

AU - Steen, Vidar M.

AU - Stein, Dan J.

AU - Strike, Lachlan T.

AU - Teumer, Alexander

AU - Thalamuthu, Anbupalam

AU - Thomopoulos, Sophia I.

AU - Tordesillas-Gutiérrez, Diana

AU - Trollor, Julian N.

AU - Uhlmann, Anne

AU - Vajdi, Ariana

AU - van ’t Ent, Dennis

AU - van Amelsvoort, Therese

AU - van den Bree, Marianne B.M.

AU - van der Meer, Dennis

AU - Vázquez-Bourgon, Javier

AU - Villalón-Reina, Julio E.

AU - Völker, Uwe

AU - Völzke, Henry

AU - Vorstman, Jacob A.S.

AU - Westlye, Lars T.

AU - Williams, Nigel

AU - Wittfeld, Katharina

AU - Wright, Margaret J.

AU - Thompson, Paul M.

AU - Andreassen, Ole A.

AU - Linden, David E.J.

PY - 2025/10

Y1 - 2025/10

N2 - Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

AB - Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

KW - Autism

KW - Neuroimaging

KW - Psychiatric disorders

KW - Schizophrenia

KW - Structural imaging

UR - https://www.scopus.com/pages/publications/105013750187

U2 - 10.1016/j.bpsc.2025.05.010

DO - 10.1016/j.bpsc.2025.05.010

M3 - Article

C2 - 40414598

AN - SCOPUS:105013750187

SN - 2451-9022

VL - 10

SP - 1093

EP - 1106

JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

IS - 10

ER -

Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology

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