TY - JOUR
T1 - Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence
AU - Kopal, Jakub
AU - Kumar, Kuldeep
AU - Saltoun, Karin
AU - Modenato, Claudia
AU - Moreau, Clara A.
AU - Martin-Brevet, Sandra
AU - Huguet, Guillaume
AU - Jean-Louis, Martineau
AU - Martin, Charles Olivier
AU - Saci, Zohra
AU - Younis, Nadine
AU - Tamer, Petra
AU - Douard, Elise
AU - Maillard, Anne M.
AU - Rodriguez-Herreros, Borja
AU - Pain, Aurèlie
AU - Richetin, Sonia
AU - Kushan, Leila
AU - Silva, Ana I.
AU - van den Bree, Marianne B.M.
AU - Linden, David E.J.
AU - Owen, Michael J.
AU - Hall, Jeremy
AU - Lippé, Sarah
AU - Draganski, Bogdan
AU - Sønderby, Ida E.
AU - Andreassen, Ole A.
AU - Glahn, David C.
AU - Thompson, Paul M.
AU - Bearden, Carrie E.
AU - Jacquemont, Sébastien
AU - Bzdok, Danilo
N1 - Funding Information:
D.B. was supported by the Brain Canada Foundation, through the Canada Brain Research Fund, with the financial support of Health Canada, the National Institutes of Health (NIH R01 AG068563A, NIH R01 R01DA053301-01A1), the Canadian Institute of Health Research (CIHR 438531, CIHR 470425), the Healthy Brains Healthy Lives initiative (Canada First Research Excellence fund), Google (Research Award, Teaching Award) and by the CIFAR Artificial Intelligence Chairs programme (Canada Institute for Advanced Research). This research was supported by Calcul Quebec ( http://www.calculquebec.ca ) and Compute Canada ( http://www.computecanada.ca ), the Brain Canada Multi-Investigator initiative, the Canadian Institutes of Health Research, CIHR_400528, the Institute of Data Valorization (IVADO) through the Canada First Research Excellence Fund, Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund. S.J. is a recipient of a Canada Research Chair in neurodevelopmental disorders and a chair from the Jeanne et Jean Louis Levesque Foundation. The Cardiff CNV cohort was supported by the Wellcome Trust Strategic Award ‘DEFINE’ and the National Centre for Mental Health with funds from Health and Care Research Wales (code 100202/Z/12/Z). The CHUV cohort was supported by the SNF (Maillard Anne, Project PMPDP3 171331). Data from the UCLA cohort provided by C.E.B. (participants with 22q11.2 deletions or duplications and controls) were supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, R03MH105808) and the Simons Foundation (SFARI Explorer Award). K.K. was supported by the Institute of Data Valorization (IVADO) Postdoctoral Fellowship programme through the Canada First Research Excellence Fund. I.E.S. was supported by the Research Council of Norway (No. 223273), South-Eastern Norway Regional Health Authority (No. 2020060), European Union’s Horizon2020 Research and Innovation Programme (CoMorMent project; Grant No. 847776) and Kristian Gerhard Jebsen Stiftelsen (SKGJ-MED-021). We thank all of the families participating at the Simons Searchlight sites and the 16p11.2 European Consortium, Simons Searchlight Consortium. We appreciate obtaining access to brain-imaging and phenotypic data on SFARI Base. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.
Funding Information:
D.B. was supported by the Brain Canada Foundation, through the Canada Brain Research Fund, with the financial support of Health Canada, the National Institutes of Health (NIH R01 AG068563A, NIH R01 R01DA053301-01A1), the Canadian Institute of Health Research (CIHR 438531, CIHR 470425), the Healthy Brains Healthy Lives initiative (Canada First Research Excellence fund), Google (Research Award, Teaching Award) and by the CIFAR Artificial Intelligence Chairs programme (Canada Institute for Advanced Research). This research was supported by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca), the Brain Canada Multi-Investigator initiative, the Canadian Institutes of Health Research, CIHR_400528, the Institute of Data Valorization (IVADO) through the Canada First Research Excellence Fund, Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund. S.J. is a recipient of a Canada Research Chair in neurodevelopmental disorders and a chair from the Jeanne et Jean Louis Levesque Foundation. The Cardiff CNV cohort was supported by the Wellcome Trust Strategic Award ‘DEFINE’ and the National Centre for Mental Health with funds from Health and Care Research Wales (code 100202/Z/12/Z). The CHUV cohort was supported by the SNF (Maillard Anne, Project PMPDP3 171331). Data from the UCLA cohort provided by C.E.B. (participants with 22q11.2 deletions or duplications and controls) were supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, R03MH105808) and the Simons Foundation (SFARI Explorer Award). K.K. was supported by the Institute of Data Valorization (IVADO) Postdoctoral Fellowship programme through the Canada First Research Excellence Fund. I.E.S. was supported by the Research Council of Norway (No. 223273), South-Eastern Norway Regional Health Authority (No. 2020060), European Union’s Horizon2020 Research and Innovation Programme (CoMorMent project; Grant No. 847776) and Kristian Gerhard Jebsen Stiftelsen (SKGJ-MED-021). We thank all of the families participating at the Simons Searchlight sites and the 16p11.2 European Consortium, Simons Searchlight Consortium. We appreciate obtaining access to brain-imaging and phenotypic data on SFARI Base. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41562-023-01541-9
DO - 10.1038/s41562-023-01541-9
M3 - Article
C2 - 36864136
SN - 2397-3374
VL - 7
SP - 1001
EP - 1017
JO - Nature human behaviour
JF - Nature human behaviour
IS - 6
ER -