Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence

Kopal, Jakub, Kumar, Kuldeep, Saltoun, Karin, Modenato, Claudia, Moreau, Clara A., Martin-Brevet, Sandra, Huguet, Guillaume, Jean-Louis, Martineau, Martin, Charles-Olivier, Saci, Zohra, Younis, Nadine, Tamer, Petra, Douard, Elise, Maillard, Anne M., Rodriguez-Herreros, Borja, Pain, Aurèlie, Richetin, Sonia, Kushan, Leila, Silva, Ana I. ORCID: https://orcid.org/0000-0002-1184-4909, van den Bree, Marianne B. M. ORCID: https://orcid.org/0000-0002-4426-3254, Linden, David E. J. ORCID: https://orcid.org/0000-0002-5638-9292, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009, Lippé, Sarah, Draganski, Bogdan, Sønderby, Ida E., Andreassen, Ole A., Glahn, David C., Thompson, Paul M., Bearden, Carrie E., Jacquemont, Sébastien and Bzdok, Danilo 2023. Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence. Nature Human Behaviour 7 , pp. 1001-1007. 10.1038/s41562-023-01541-9

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Abstract

Copy number variations (CNVs) are rare genomic deletions and duplications that can affect brain and behaviour. Previous reports of CNV pleiotropy imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, existing studies have primarily examined single CNV loci in small clinical cohorts. It remains unknown, for example, how distinct CNVs escalate vulnerability for the same developmental and psychiatric disorders. Here we quantitatively dissect the associations between brain organization and behavioural differentiation across 8 key CNVs. In 534 CNV carriers, we explored CNV-specific brain morphology patterns. CNVs were characteristic of disparate morphological changes involving multiple large-scale networks. We extensively annotated these CNV-associated patterns with ~1,000 lifestyle indicators through the UK Biobank resource. The resulting phenotypic profiles largely overlap and have body-wide implications, including the cardiovascular, endocrine, skeletal and nervous systems. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Publisher:	Nature Research
ISSN:	2397-3374
Date of First Compliant Deposit:	4 May 2023
Date of Acceptance:	30 January 2023
Last Modified:	07 Nov 2023 23:15
URI:	https://orca.cardiff.ac.uk/id/eprint/158483

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