Penetrance of neurodevelopmental copy number variants is associated with variations in cortical morphology

Silva, Ana ORCID: https://orcid.org/0000-0002-1184-4909, Sønderby, Ida, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Abdellaoui, Abdel, Agartz, Ingrid, Ames, David, Armstrong, Nicola, Artiges, Eric, Banaschewski, Tobias, Basset, Anne, Bearden, Carrie, Blangero, John, Boen, Rune, Boomsma, Dorret, Bulow, Robin, Butcher, Nancy, Calhoun, Vince, Campbell, Linda, Chow, Eva, Ciufolini, Simone, Craig, Michael, Crespo-farrocco, Benedicto, Cunningham, Adam, Dalvie, Shareefa, Daly, Eileen, Dazzan, Paola, de Geus, Eco, Zubicaray, Greig, Doherty, Joanne, Donohoe, Gary, Drakesmith, Mark, Espeseth, Thomas, Frouin, Vincent, Garavan, Hugh, Glahn, David, Goodrich-Hunsaker, Naomi, Gowland, Penny, Grabe, Hans, Grigis, Antonie, Gudbrandsen, Maria, Gutman, Boris, Haavik, Jan, Haberg, Asta, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009, Heinz, Andreas, Hoh mann, Sarah, Hottenga, Jouke-Jan, Jacquemont, Sebastien, Jahanshad, Neda, Jones, Rachel, Jones, Derek ORCID: https://orcid.org/0000-0003-4409-8049, Jonsson, Erik, Koops, Sanne, Kumar, Kuldeep, Le Hellard, Stephanie, Lemaitre, Herve, Liu, Jingyu, Lundervold, Astri, Martinot, Jean-Luc, Mather, Karen, McDonald-McGinn, Donna, McMahon, Katie, McRae, Allan, Medland, Sarah, Moreau, Clara, Murphy, Kieran, Murphy, Declan, Murray, Robin, Nees, Frauke, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Papadopoulos Orfanos, Diimitri, Paus, Tomas, Poustka, Luise, Reis Marques, Tiago, Roalf, David, Sachdev, Perminder, Scheffler, Freda, Schmitt, Eric, Schumann, Gunter, Steen, Vidar, Stein, Dan, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbupalam, Thomopoulos, Sophia, Tordesillas-Gutierrez, Diana, Trolbr, Julian, Uhlmann, Anne, Vajdi, Ariana, Van't Ent, Dennis, Van Amelsvoort, Therese, van den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254, van der Meer, Dennis, Vazquez-Bourgon, Javier, Villalon-Reina, Julio, Volker, Uwe, Volzke, Henry, Vorstman, Jacob, Westlye, Lars, Williams, Nigel ORCID: https://orcid.org/0000-0003-1177-6931, Wittfeld, Katharina, Wright, Margaret, Thompson, Paul, Andreassen, Ole and Linden, David ORCID: https://orcid.org/0000-0002-5638-9292 2025. Penetrance of neurodevelopmental copy number variants is associated with variations in cortical morphology. Biological Psychiatry 10.1016/j.bpsc.2025.05.010

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Abstract

BACKGROUND Copy number variants (CNVs) increase risk for neurodevelopmental conditions. The neurobiological mechanisms linking these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals carrying CNVs are associated with their degree of penetrance. METHODS We investigated if 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-CNV consortium. In the main analyses, we included 9,268 individuals (aged 7 to 90 years, 54% females), 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 non-carriers. CNV-penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk to develop 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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
ISSN:	0006-3223
Date of First Compliant Deposit:	10 June 2025
Date of Acceptance:	19 May 2025
Last Modified:	10 Jun 2025 09:31
URI:	https://orca.cardiff.ac.uk/id/eprint/178819

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