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1. Using rare genetic mutations to revisit structural brain asymmetry

Author

Jakub Kopal, Kuldeep Kumar, Kimia Shafighi, Karin Saltoun, Claudia Modenato, Clara A. Moreau, Guillaume Huguet, Martineau Jean-Louis, Charles-Olivier Martin, Zohra Saci, Nadine Younis, Elise Douard, Khadije Jizi, Alexis Beauchamp-Chatel, Leila Kushan, Ana I. Silva, Marianne B. M. van den Bree, David E. J. Linden, Michael J. Owen, Jeremy Hall, Sarah Lippé, Bogdan Draganski, Ida E. Sønderby, Ole A. Andreassen, David C. Glahn, Paul M. Thompson, Carrie E. Bearden, Robert Zatorre, Sébastien Jacquemont, and Danilo Bzdok

Subjects
Science
Abstract

Abstract Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Published
2024
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2. Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability

Author

Zoe Schmilovich, Vincent-Raphaël Bourque, Elise Douard, Guillaume Huguet, Cécile Poulain, Jay P. Ross, Paria Alipour, Charles-Étienne Castonguay, Nadine Younis, Martineau Jean-Louis, Zohra Saci, Zdenka Pausova, Tomas Paus, Gunter Schuman, David Porteous, Gail Davies, Paul Redmond, Sarah E. Harris, Ian J. Deary, Heather Whalley, Caroline Hayward, Patrick A. Dion, Sébastien Jacquemont, and Guy A. Rouleau

Subjects
CNV (copy number variant), polygenic risk score (PRS), ASD autism spectrum disorders, cognitive abilities, intelligence quotient (IQ), Psychiatry, RC435-571
Abstract

IntroductionRare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability.MethodsIn a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability.ResultsBottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD.DiscussionOur findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.

Published
2024
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3. Author Correction: Using rare genetic mutations to revisit structural brain asymmetry

Author

Jakub Kopal, Kuldeep Kumar, Kimia Shafighi, Karin Saltoun, Claudia Modenato, Clara A. Moreau, Guillaume Huguet, Martineau Jean-Louis, Charles-Olivier Martin, Zohra Saci, Nadine Younis, Elise Douard, Khadije Jizi, Alexis Beauchamp-Chatel, Leila Kushan, Ana I. Silva, Marianne B. M. van den Bree, David E. J. Linden, Michael J. Owen, Jeremy Hall, Sarah Lippé, Bogdan Draganski, Ida E. Sønderby, Ole A. Andreassen, David C. Glahn, Paul M. Thompson, Carrie E. Bearden, Robert Zatorre, Sébastien Jacquemont, and Danilo Bzdok

Subjects
Science
Published
2024
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4. Effects of eight neuropsychiatric copy number variants on human brain structure

Author

Claudia Modenato, Kuldeep Kumar, Clara Moreau, Sandra Martin-Brevet, Guillaume Huguet, Catherine Schramm, Martineau Jean-Louis, Charles-Olivier Martin, Nadine Younis, Petra Tamer, Elise Douard, Fanny Thébault-Dagher, Valérie Côté, Audrey-Rose Charlebois, Florence Deguire, Anne M. Maillard, Borja Rodriguez-Herreros, Aurèlie Pain, Sonia Richetin, p11.2 European Consortium, Simons Searchlight Consortium, Lester Melie-Garcia, Leila Kushan, Ana I. Silva, Marianne B. M. van den Bree, David E. J. Linden, Michael J. Owen, Jeremy Hall, Sarah Lippé, Mallar Chakravarty, Danilo Bzdok, Carrie E. Bearden, Bogdan Draganski, and Sébastien Jacquemont

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.

Published
2021
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5. Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Author

Clara A Moreau, Kuldeep Kumar, Annabelle Harvey, Guillaume Huguet, Sebastian G W Urchs, Laura M Schultz, Hanad Sharmarke, Khadije Jizi, Charles-Olivier Martin, Nadine Younis, Petra Tamer, Jean-Louis Martineau, Pierre Orban, Ana Isabel Silva, Jeremy Hall, Marianne B M van den Bree, Michael J Owen, David E J Linden, Sarah Lippé, Carrie E Bearden, Laura Almasy, David C Glahn, Paul M Thompson, Thomas Bourgeron, Pierre Bellec, Sebastien Jacquemont, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), Université de Montréal (UdeM), McGill University = Université McGill [Montréal, Canada], Children’s Hospital of Philadelphia (CHOP ), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), Cardiff University, Maastricht University [Maastricht], University of California [Los Angeles] (UCLA), University of California (UC), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California (UC)-University of California (UC), University of Pennsylvania, Keck School of Medicine [Los Angeles], University of Southern California (USC), This research was supported by Compute Canada (ID 3037 and gsf-624), the Brain Canada Multi-Investigator Research Initiative (MIRI), Canada First Research Excellence Fund, IVADO, Canada First Research Excellence Fund (Healthy Brain Healthy Lives) (S.J.). S.J. is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. This work was supported by a grant from the ‘Fondation Brain Canada’ Multi-Investigator initiative (S.J.) and a grant from The Canadian Institutes of Health Research (CIHR 400528, S.J.). 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 Swiss National Science Foundation (Maillard Anne, Project, PMPDP3 171331). Data from the UCLA cohort provided by C.E.B. (participants with 22q11.2 deletions or duplications and controls) was supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, 1U01MH119736, R21MH116473) and the Simons Foundation (SFARI Explorer Award). Finally, data from another study were obtained through the OpenFMRI project (http://openfmri.org) from the Consortium for Neuropsychiatric Phenomics (CNP), which was supported by National Institutes of Health Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271 and PL1NS062410. P.B. is a fellow (‘Chercheur boursier Junior 2’) of the ‘Fonds de recherche du Québec—Santé’, Data preprocessing and analyses were supported in part by the Courtois foundation (P.B.). This work was supported by Simons Foundation grant nos. SFARI219193 and SFARI274424. We thank all of the families at the participating SVIP (VIP) sites, as well as the Simons VIP Consortium. We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons VIP population dataset described in this study by applying at https://base.sfari.org. We are grateful to all families who participated in the 16p11.2 European Consortium. P.M.T. was funded in part by the National Institutes of Health grants R01MH116147, P41EB015922, R01MH111671 and U01 AG068057. P.T. received the Canadian Institute of Health Research (CIHR) Scholarship., RS: MHeNs - R2 - Mental Health, Psychiatry 1, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, and RS: MHeNs - R3 - Neuroscience

Subjects
copy-number variant, pleiotropy, functional connectivity, autism spectrum disorder, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), psychiatry
Abstract

Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic—rFunctional connectivity = 0.71 [0.40–0.87] and rTranscriptomic—rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks.

Published
2023

6. Using rare genetic mutations to revisit structural brain asymmetry

Author

Jakub Kopal, Kuldeep Kumar, Kimia Shafighi, Karin Saltoun, Claudia Modenato, Clara A. Moreau, Guillaume Huguet, Martineau Jean-Louis, Charles-Olivier Martin, Zohra Saci, Nadine Younis, Elise Douard, Khadije Jizi, Alexis Beauchamp-Chatel, Leila Kushan, Ana I. Silva, Marianne B. M. van den Bree, David E. J. Linden, Michael J. Owen, Jeremy Hall, Sarah Lippé, Bogdan Draganski, Ida E. Sønderby, Ole A. Andreassen, David C. Glahn, Paul M. Thompson, Carrie E. Bearden, Robert Zatorre, Sébastien Jacquemont, and Danilo Bzdok

Subjects
Article
Abstract

Asymmetry between the left and right brain is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variant studies, which typically exert small effects on brain phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We quantitatively dissected the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior mapping highlights the consequences of genetically controlled brain lateralization on human-defining cognitive traits.

Published
2023

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

Author

Jakub Kopal, Kuldeep Kumar, Karin Saltoun, Claudia Modenato, Clara A. Moreau, Sandra Martin-Brevet, Guillaume Huguet, Martineau Jean-Louis, Charles-Olivier Martin, Zohra Saci, Nadine Younis, Petra Tamer, Elise Douard, Anne M. Maillard, Borja Rodriguez-Herreros, Aurèlie Pain, Sonia Richetin, Leila Kushan, Ana I. Silva, Marianne B. M. van den Bree, David E. J. Linden, Michael J. Owen, Jeremy Hall, Sarah Lippé, Bogdan Draganski, Ida E. Sønderby, Ole A. Andreassen, David C. Glahn, Paul M. Thompson, Carrie E. Bearden, Sébastien Jacquemont, and Danilo Bzdok

Subjects
Behavioral Neuroscience, Social Psychology, Experimental and Cognitive Psychology
Published
2023

8. Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry

Author

Clara A. Moreau, Annabelle Harvey, Kuldeep Kumar, Guillaume Huguet, Sebastian G.W. Urchs, Elise A. Douard, Laura M. Schultz, Hanad Sharmarke, Khadije Jizi, Charles-Olivier Martin, Nadine Younis, Petra Tamer, Thomas Rolland, Jean-Louis Martineau, Pierre Orban, Ana Isabel Silva, Jeremy Hall, Marianne B.M. van den Bree, Michael J. Owen, David E.J. Linden, Aurelie Labbe, Sarah Lippé, Carrie E. Bearden, Laura Almasy, David C. Glahn, Paul M. Thompson, Thomas Bourgeron, Pierre Bellec, Sebastien Jacquemont, RS: MHeNs - R2 - Mental Health, Psychiatry 1, RS: MHeNs School for Mental Health and Neuroscience, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, RS: MHeNs - R3 - Neuroscience, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Children’s Hospital of Philadelphia (CHOP ), Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal (CRIUSMM), Université de Montréal (UdeM), Cardiff University, Maastricht University [Maastricht], HEC Montréal (HEC Montréal), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Pennsylvania, Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), and This research was supported by Compute Canada (ID 3037 and gsf-624), the Brain Canada Multi investigator research initiative (MIRI), Canada First Research Excellence Fund, Institute of Data Valorization, Healthy Brain Healthy Lives (Dr. Jacquemont). Dr. Jacquemont is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. This work was supported by a grant from the Brain Canada Multi-Investigator initiative (Dr. Jacquemont) and a grant from The Canadian Institutes of Health Research (CIHR 400528, Dr. Jacquemont). Clara Moreau and Thomas Bourgeron are supported by AIMS-2-TRIALS - which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394. 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). Data from the UCLA cohort provided by Dr. Bearden (participants with 22q11.2 deletions or duplications and controls) was supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, 1U01MH119736, R21MH116473 ), and the Simons Foundation (SFARI Explorer Award). Finally, data from another study were obtained through the OpenFMRI project (http://openfmri.org) from the Consortium for Neuropsychiatric Phenomics (CNP), which was supported by NIH Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271, and PL1NS062410. Dr P. Bellec is a fellow ('Chercheur boursier Junior 2') of the 'Fonds de recherche du Québec - Santé', Data preprocessing and analyses were supported in part by the Courtois foundation (Dr Bellec). This work was supported by Simons Foundation Grant Nos. SFARI219193 and SFARI274424. We thank all of the families at the participating Simons Variation in Individuals Project (VIP) sites, as well as the Simons VIP Consortium. We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons VIP population dataset described in this study by applying at https://base.sfari.org. We are grateful to all families who participated in the 16p11.2 European Consortium. Dr. P. Thompson was funded in part by the U.S. NIH grants R01MH116147, P41EB015922, R01MH111671, and U01 AG068057. Ms. Petra Tamer received the Canadian Institute of Health Research (CIHR) Scholarship.

Subjects
Psychiatry, Multifactorial Inheritance, DNA Copy Number Variations, Brain, Copy number variant, Functional connectivity, Genetic Heterogeneity, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Humans, Genetic Predisposition to Disease, Polygenic score transdiagnostic approach, Autism spectrum disorder, Biological Psychiatry, Genome-Wide Association Study
Abstract

BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.

Published
2023

9. Atlas of functional connectivity relationships across rare and common genetic variants, traits, and psychiatric conditions

Author

Sarah Lippé, Carrie E. Bearden, Kuldeep Kumar, Elise Douard, Thomas Rolland, Jean-Louis Martineau, David Shin, Marianne Bernadette van den Bree, Hanad Sharmarke, Clara Moreau, Pierre Orban, Annabelle Harvey, Aurélie Labbe, Pierre Bellec, Laura M. Schultz, Guillaume Huguet, David Edmund Johannes Linden, Petra Tamer, Paul M. Thompson, Sebastian Urchs, Sébastien Jacquemont, Laura Almasy, Nadine Younis, David C. Glahn, Ana I. Silva, Anne M. Maillard, Tomasz J. Nowakowski, Thomas Bourgeron, Khadije Jizi, Charles-Olivier Martin, Michael John Owen, Jeremy Hall, Institut Pasteur [Paris] (IP), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Montréal (UdeM), McGill University = Université McGill [Montréal, Canada], Children’s Hospital of Philadelphia (CHOP ), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC), Cardiff University, Maastricht University [Maastricht], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of California [Los Angeles] (UCLA), University of Pennsylvania, Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Keck School of Medicine [Los Angeles], University of Southern California (USC), This research was supported by Compute Canada (ID 3037 and gsf-624), the Brain Canada Multi investigator research initiative (MIRI), Canada First Research Excellence Fund, Institute of Data Valorization, Healthy Brain Healthy Lives (Dr. Jacquemont). Dr. Jacquemont is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. This work was supported by a grant from the Brain Canada Multi-Investigator initiative (Dr. Jacquemont) and a grant from The Canadian Institutes of Health Research (CIHR 400528, Dr. Jacquemont). 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 Dr. Bearden (participants with 22q11.2 deletions or duplications and controls) was supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, 1U01MH119736, R21MH116473), and the Simons Foundation (SFARI Explorer Award). Finally, data from another study were obtained through the OpenFMRI project (http://openfmri.org) from the Consortium for Neuropsychiatric Phenomics (CNP), which was supported by NIH Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271, and PL1NS062410. Dr P. Bellec is a fellow ('Chercheur boursier Junior 2') of the 'Fonds de recherche du Québec - Santé', Data preprocessing and analyses were supported in part by the Courtois foundation (Dr Bellec). This work was supported by Simons Foundation Grant Nos. SFARI219193 and SFARI274424., We thank all of the families at the participating Simons Variation in Individuals Project (VIP) sites, as well as the Simons VIP Consortium. We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons VIP population dataset described in this study by applying at https://base.sfari.org. We are grateful to all families who participated in the 16p11.2 European Consortium. Dr. P. Thompson was funded in part by the U.S. NIH grants R01MH116147, P41EB015922, R01MH111671, and U01 AG068057. Ms. Petra Tamer received the Canadian Institute of Health Research (CIHR) Scholarship., Institut Pasteur [Paris], Centre de recherche du CHU Sainte-Justine [Montreal], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), University of California [San Francisco] (UCSF), University of California, and University of Pennsylvania [Philadelphia]

Subjects
0303 health sciences, medicine.medical_specialty, Multivariate analysis, Concordance, Functional connectivity, Brain morphometry, Cognition, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pleiotropy, medicine, Copy-number variation, Psychiatry, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Polygenicity and pleiotropy are key properties of the genomic architecture of psychiatric disorders. An optimistic interpretation of polygenicity is that genomic variants converge on a limited set of mechanisms at some level from genes to behavior. Alternatively, convergence may be minimal or absent.We took advantage of brain connectivity, measured by resting-state functional MRI (rs- fMRI), as well as rare and common genomic variants to understand the effects of polygenicity and pleiotropy on large-scale brain networks, a distal step from genes to behavior. We processed ten rs-fMRI datasets including 32,988 individuals, to examine connectome-wide effects of 16 copy number variants (CNVs), 10 polygenic scores, 6 cognitive and brain morphometry traits, and 4 idiopathic psychiatric conditions.Although effect sizes of CNVs on connectivity were correlated to cognition and number of genes, increasing polygenicity was associated with decreasing effect sizes on connectivity. Accordingly, the effect sizes of polygenic scores on connectivity were 6-fold lower compared to CNVs. Despite this heterogeneity of connectivity profiles, multivariate analysis identified convergence of genetic risks and psychiatric disorders on the thalamus and the somatomotor network. Based on spatial correlations with transcriptomic data, we hypothesize that excitatory thalamic neurons may be primary contributors to brain alteration profiles shared across genetic risks and conditions. Finally, pleiotropy measured by genetic and transcriptomic correlations between 38 pairs of conditions/traits showed significant concordance with connectomic correlations, suggesting a substantial causal genetic component for shared connectivity.Such findings open avenues to delineate general mechanisms - amenable to intervention - across conditions and genetic risks.One sentence summaryEffects of rare and common genomic variants on brain functional connectivity shed light on the impact of polygenicity and pleiotropy in psychiatry.

Published
2021

10. Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability

Author

Ian J. Deary, Elise Douard, Thomas Renne, Gunter Schumann, Thomas Bourgeron, W. David Hill, Sarah Lippé, Tomáš Paus, Frédérique Tihy, Khadije Jizi, Sarah E. Harris, Myriam Poirier, Nadine Younis, Catherine Schramm, Zdenka Pausova, Zohra Saci, Charles-Olivier Martin, Sébastien Jacquemont, Petra Tamer, Pauline Monin, Sherif Karama, Paul Redmond, Laura Almasy, Gail Davies, Jade England, Maude Auger, Celia M. T. Greenwood, Guillaume Huguet, David J. Porteous, Antoine Main, Géraldine Mathonnet, David C. Glahn, Sabrina Nowak, Emmanuelle Lemyre, Inga Sophia Knoth, Martineau Jean-Louis, Aurélie Labbe, Catalina Maftei, Université de Montréal (UdeM), CHU Sainte Justine [Montréal], Jewish General Hospital, HEC Montréal (HEC Montréal), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), University of Edinburgh, King‘s College London, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, McGill University = Université McGill [Montréal, Canada], Douglas Mental Health University Institute [Montréal], Children’s Hospital of Philadelphia (CHOP ), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Hartford Hospital, This research was enabled by support provided by Calcul Quebec and Compute Canada. SJ is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. CS is supported by an Institute for Data Valorization (IVADO) fellowship. PT is supported by a Canadian Institute of Health Research (CIHR) Scholarship Program. GH is supported by the Sainte-Justine Foundation, the Merit Scholarship Program for foreign students, and the Network of Applied Genetic Medicine fellowships. TB is a recipient of a chair of the Bettencourt-Schueler foundation. This work is supported by a grant from the Brain Canada Multi-Investigator initiative and CIHR grant 159734 (SJ, CMTG, TP). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study (SYS). SYS was funded by the Canadian Institutes of Health Research (TP, ZP) and the Heart and Stroke Foundation of Canada (ZP). Funding for the project was provided by the Wellcome Trust. This work was also supported by an NIH award U01 MH119690 granted to LA, SJ, and DG and U01 MH119739., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, DNA Copy Number Variations, Gene Dosage, Biology, Gene dosage, Genome, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cognition, 0302 clinical medicine, medicine, Humans, genetics, Copy-number variation, Molecular Biology, Gene, Intelligence Tests, Genetics, Intelligence quotient, [SCCO.NEUR]Cognitive science/Neuroscience, Inheritance (genetic algorithm), medicine.disease, Psychiatry and Mental health, psychiatric disorders, 030104 developmental biology, Autism, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

International audience; Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

Published
2021

11. Neuropsychiatric copy number variants exert shared effects on human brain structure

Author

Sandra Martin-Brevet, Kuldeep Kumar, Clara Moreau, M. Mallar Chakravarty, Florence Deguire, Elise Douard, Guillaume Huguet, Sarah Lippé, Carrie E. Bearden, Sébastien Jacquemont, Fanny Thébault-Dagher, Claudia Modenato, Sonia Richetin, Charlebois A, Danilo Bzdok, Côté, Bogdan Draganski, Aurélie Pain, Lester Melie-Garcia, van den Bree Mb, Ana I. Silva, Jean-Louis Martineau, Nadine Younis, Petra Tamer, Anne M. Maillard, Charles-Olivier Martin, Jeremy Hall, Michael John Owen, Leila Kushan, David E. J. Linden, Catherine Schramm, and Borja Rodriguez-Herreros

Subjects
Genetics, 0303 health sciences, Mutation, Brain morphometry, Human brain, Biology, medicine.disease, medicine.disease_cause, 03 medical and health sciences, Brain anatomy, 0302 clinical medicine, medicine.anatomical_structure, Neuroimaging, Schizophrenia, mental disorders, medicine, Autism, Copy-number variation, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

BackgroundCopy Number Variants (CNVs) associated with autism and schizophrenia have large effects on brain anatomy. Yet, neuroimaging studies have been conducted one mutation at a time. We hypothesize that neuropsychiatric CNVs may exert general effects on brain morphometry because they confer risk for overlapping psychiatric conditions.MethodsWe analyzed T1-weighted MRIs and characterized shared patterns on brain anatomy across 8 neuropsychiatric CNVs. Clinically ascertained samples included 1q21.1 (n=48), 16p11.2 (n=156), or 22q11.2 (n=96) and 331 non-carriers. Non-clinically ascertained samples from the UK Biobank included 1q21.1 (n=19), 16p11.2 (n=8), 22q11.2 (n=9), 15q11.2 (n=148) and 965 non-carriers. Canonical correlation analysis (CCA) and univariate models were used to interrogate brain morphometry changes across 8 CNVs.ResultsEight CNVs affect regional brain volumes along two main gene-morphometry dimensions identified by CCA. While fronto-temporal regions contributed to dimension 1, dimension 2 was driven by subcortical, parietal and occipital regions. Consistently, voxel-wise whole-brain analyses identified the same regions involved in patterns of alteration present across the 4 deletions and duplications. These neuroanatomical patterns are similar to those observed in cross-psychiatric disorder meta-analyses. Deletions and duplications at all 4 loci show mirror effects at either the global and/or the regional level.ConclusionNeuropsychiatric CNVs share neuroanatomical signatures characterized by a parsimonious set of brain dimensions. The latter may underlie the risk conferred by CNVs for a similar spectrum of neuropsychiatric conditions.

Published
2020

12. Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Author

Guillaume Huguet, Catherine Schramm, Elise Douard, Tamer Petra, Antoine Main, Pauline Monin, Jade England, Khadije Jizi, Thomas Renne, Myriam Poirier, Sabrina Nowak, Charles-Olivier Martin, Nadine Younis, Inga Sophia Knoth, Martineau Jean-Louis, Zohra Saci, Maude Auger, Frédérique Tihy, Géraldine Mathonnet, Catalina Maftei, France Léveillé, David Porteous, Gail Davies, Paul Redmond, Sarah E. Harris, W. David Hill, Emmanuelle Lemyre, Gunter Schumann, Thomas Bourgeron, Zdenka Pausova, Tomas Paus, Sherif Karama, Sarah Lippe, Ian J. Deary, Laura Almasy, Aurélie Labbe, David Glahn, Celia M.T. Greenwood, and Sébastien Jacquemont

Subjects
Genetics, Regulation of gene expression, 0303 health sciences, Inheritance (genetic algorithm), Biology, medicine.disease, Gene dosage, Genome, 03 medical and health sciences, 0302 clinical medicine, medicine, Autism, Copy-number variation, Haploinsufficiency, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well.Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency.We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

Published
2020

13. The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs

Author

Claudia Modenato, Amy Lin, Sarah Lippé, Carrie E. Bearden, Aurélie Labbe, David Edmund Johannes Linden, Marianne Bernadette van den Bree, Jean-Louis Martineau, Nadine Younis, Pierre Bellec, Petra Tamer, Sebastian Urchs, Hanad Sharmarke, Aia E. Jønch, Elise Douard, Khadije Jizi, Sandra Martin-Brevet, Clara Moreau, Jeremy Hall, Anne M. Maillard, Sébastien Jacquemont, Charles-Olivier Martin, Celia M. T. Greenwood, Guillaume Huguet, Pierre Orban, Kumar Kuldeep, Paul M. Thompson, Michael John Owen, and Ana I. Silva

Subjects
Genetics, 0303 health sciences, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system diseases, Cognition, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Schizophrenia, Basal ganglia, mental disorders, medicine, Autism, Attention deficit hyperactivity disorder, Copy-number variation, Haploinsufficiency, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Large effect-size mutations such as copy number variants (CNVs) have the potential to provide key insights into the underlying biological mechanisms linking deleterious genetic variants to brain architecture and neuropsychiatric disorders. To date, the effect of CNVs on functional brain connectivity remains mostly unstudied, and findings are derived from analyses conducted one mutation at a time. The lack of systematic cross-CNV comparisons hinders our understanding of any potential general mechanisms linking CNVs to effects on brain organization. We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, and 4 neutral-effect CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity. The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. We reported architecture similarities between individuals with idiopathic psychiatric conditions and high-risk neuropsychiatric-CNVs, predominantly in the thalamus, the posterior cingulate cortex, and the anterior insula. We identified a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders. We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.

Published
2020
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