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206 results on '"Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1))"'

1. 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

2. Inpatient target discharge weight for early-onset anorexia nervosa: Restoring premorbid BMI percentile to improve height prognosis

Author: A. Ayrolles, J. Clarke, M. Dechaux, A. Lefebvre, A. Cohen, C. Stordeur, H. Peyre, A. Bargiacchi, N. Godart, H. Watson, R. Delorme, Hôpital Robert Debré Paris, Hôpital Robert Debré, 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 Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Fondation Santé des Etudiants de France, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Curtin University [Perth], Planning and Transport Research Centre (PATREC), and The University of Western Australia (UWA)
Subjects: Early-onset, Nutrition and Dietetics, Height prognosis, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Anorexia nervosa, Weight suppression
Abstract: International audience; Objective: Early-onset anorexia nervosa (EO-AN) is characterized by restricted food intake leading to low body weight, emerging before 14 years old. Most patients reaching a target body mass index (BMI) around the 25th percentile at hospitalization discharge display an incomplete prospective height catch-up. A better understanding of height prognosis determinants is required. Methods: In 74 children with an EO-AN, we collected height and weight premorbidly, at hospitalization, and at discharge, 6 months, 12 months, and at longer-term follow-up of 36 months. We defined a height prognosis parameter (HPP) as the difference between the height percentile at follow-up times and the premorbid height percentile. We explored the relationship between weight parameters and height catch-up at follow-up with linear regression analyses. Results: A higher weight suppression (WS) - i.e., difference between premorbid and current BMI - at admission and discharge was associated with lower HPP - i.e., a greater loss of height - at 12 months and 36 months follow-up. Similarly, a higher premorbid BMI percentile was associated with a lower HPP at 12 and 36 months. Conclusion: Target discharge weight for EO-AN patients should be tailored and based on premorbid BMI trajectory to improve height prognosis.
Published: 2023

3. Impact of the gut microbiome on nicotine’s motivational effects and glial cells in the ventral tegmental area in male mice

Author: Alina Lakosa, Anaïs Rahimian, Flavio Tomasi, Fabio Marti, Lauren M. Reynolds, Léa Tochon, Vincent David, Anne Danckaert, Candice Canonne, Sylvana Tahraoui, Fabrice de Chaumont, Benoît Forget, Uwe Maskos, Morgane Besson, Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Plateforme technologique Bioimagerie Photonique - Photonic BioImaging Technologic Platform, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), 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), This work was supported by the Institut Pasteur, Paris (GPF Microbes and Brain, project 'µBIOTADDICT'). UtechS PBI/C2RT is part of the France BioImaging infrastructure supported by the French National Research Agency (ANR-10-INSB-04-01, 'Investments for the future') and is supported by Conseil de la Region Ile-de-France (Domaine d’Intérêt Majeur DIM1HEALTH) and by Fondation Française pour la Recherche Médicale (Programme Grands Equipements)., and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Subjects: Pharmacology, Psychiatry and Mental health, [SDV]Life Sciences [q-bio]
Abstract: International audience; A link between gut dysbiosis and the pathogenesis of brain disorders has been identified. A role for gut bacteria in drug reward and addiction has been suggested but very few studies have investigated their impact on brain and behavioral responses to addictive drugs so far. In particular, their influence on nicotine’s addiction-like processes remains unknown. In addition, evidence shows that glial cells shape the neuronal activity of the mesolimbic system but their regulation, within this system, by the gut microbiome is not established. We demonstrate that a lack of gut microbiota in male mice potentiates the nicotine-induced activation of sub-regions of the mesolimbic system. We further show that gut microbiota depletion enhances the response to nicotine of dopaminergic neurons of the posterior ventral tegmental area (pVTA), and alters nicotine’s rewarding and aversive effects in an intra-VTA self-administration procedure. These effects were not associated with gross behavioral alterations and the nicotine withdrawal syndrome was not impacted. We further show that depletion of the gut microbiome modulates the glial cells of the mesolimbic system. Notably, it increases the number of astrocytes selectively in the pVTA, and the expression of postsynaptic density protein 95 in both VTA sub-regions, without altering the density of the astrocytic glutamatergic transporter GLT1. Finally, we identify several sub-populations of microglia in the VTA that differ between its anterior and posterior sub-parts, and show that they are re-organized in conditions of gut microbiota depletion. The present study paves the way for refining our understanding of the pathophysiology of nicotine addiction.
Published: 2023

4. The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression

Author: Dorothea L, Floris, Han, Peng, Varun, Warrier, Michael V, Lombardo, Charlotte M, Pretzsch, Clara, Moreau, Alex, Tsompanidis, Weikang, Gong, Maarten, Mennes, Alberto, Llera, Daan, van Rooij, Marianne, Oldehinkel, Natalie J, Forde, Tony, Charman, Julian, Tillmann, Tobias, Banaschewski, Carolin, Moessnang, Sarah, Durston, Rosemary J, Holt, Christine, Ecker, Flavio, Dell'Acqua, Eva, Loth, Thomas, Bourgeron, Declan G M, Murphy, Andre F, Marquand, Meng-Chuan, Lai, Jan K, Buitelaar, Simon, Baron-Cohen, Christian F, Beckmann, Universität Zürich [Zürich] = University of Zurich (UZH), Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, 6525 EN Nijmegen., Wellcome Trust Centre for Integrative Neuroimaging (WIN - FMRIB), University of Oxford, University of Cambridge [UK] (CAM), Autism Research Centre [Cambridge, Royaume-Uni], University of Trento [Trento], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, 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), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Monash University [Melbourne], Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], University Hospital Mannheim | Universitätsmedizin Mannheim, Heidelberg University, University Medical Center [Utrecht], Curtin University [Perth], Planning and Transport Research Centre (PATREC), and Sackler Institute of Translational Neurodevelopment [London]
Subjects: Machine Learning, Psychiatry and Mental health, Gender Differences, Neuroanatomy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Autism Spectrum Disorder, Neurodevelopmental Disorders, 130 000 Cognitive Neurology & Memory, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], 220 Statistical Imaging Neuroscience, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Brain Imaging Techniques
Abstract: Item does not contain fulltext OBJECTIVE: The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. METHODS: Using a novel deep learning framework trained to predict biological sex based on T(1)-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T(1)-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age). RESULTS: Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types. CONCLUSIONS: The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.
Published: 2023

5. Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome

Author: Michael Schön, Pablo Lapunzina, Julián Nevado, Teresa Mattina, Cecilia Gunnarsson, Kinga Hadzsiev, Chiara Verpelli, Thomas Bourgeron, Sarah Jesse, Conny M.A. van Ravenswaaij-Arts, Raoul C. Hennekam, General Paediatrics, APH - Quality of Care, Universität Ulm - Ulm University [Ulm, Allemagne], Hospital Universitario La Paz, CIBER de Enfermedades Raras (CIBERER), University of Catania [Italy], Linköping University (LIU), University of Pecs, Istituto di Neuroscienze - Institute of Neuroscience [Milan, Italy] (CNR), Università degli Studi di Milano = University of Milan (UNIMI)-Consiglio Nazionale delle Ricerche [Milano] (CNR), 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), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Groningen [Groningen], VU University Medical Center [Amsterdam], This study has been supported by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) represented by Klea Vyshka. Funding was also obtained from the European Union’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP N° 825575., and This publication has been supported by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA). ERN-ITHACA is partly co-funded by the Health Program of the European Union. We thank for the comprehensive help of Klea Vyshka from ERN-ITHACA. We thank the American guideline consortium for discussions and support.
Subjects: Genotype-phenotype correlation, 22q13 deletion syndrome, Clinical trials, SHANK3, Genetics, Natural history, Phelan-McDermid syndrome, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PMS, General Medicine, Genetics (clinical)
Abstract: International audience; Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2–33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.
Published: 2023

6. Phenotypic effects of genetic variants associated with autism

Author: Rolland, Thomas, Cliquet, Freddy, Anney, Richard, Moreau, Clara, Traut, Nicolas, Mathieu, Alexandre, Huguet, Guillaume, Duan, Jinjie, Warrier, Varun, Portalier, Swan, Dry, Louise, Leblond, Claire, Douard, Elise, Amsellem, Frédérique, Malesys, Simon, Maruani, Anna, Toro, Roberto, Børglum, Anders D., Grove, Jakob, Baron-Cohen, Simon, Packer, Alan, Chung, Wendy, Jacquemont, Sébastien, Delorme, Richard, Bourgeron, Thomas, 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), Cardiff University, Centre de Recherches Interdisciplinaires (CRI), 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], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Cambridge [UK] (CAM), Université de Montréal (UdeM), Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Simons Foundation, Columbia University Medical Center (CUMC), Columbia University [New York], S.J. is supported by Calcul Quebec and Compute Canada, NIH U01 grant for CAMP (1U01MH119690–01), the Canadian Institutes of Health Research, CIHR_400528, and the Institute of Data Valorization (IVADO) 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. This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Eranet-Neuron (ALTRUISM) and the GenMed Labex, AIMS-2-TRIALS, which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the Horizon Europe programs CANDY and R2D2-MH under grant agreement nos. 847818 and 101057385. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. Additionally, for UK partners, the work was funded by UK Research and Innovation under the UK government’s Horizon Europe funding guarantee (grant no.10039383). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003) and the Universities and University Hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). S.B.C. received funding from the Wellcome Trust 214322\Z\18\Z, support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. S.B.C. also received funding from the Autism Centre of Excellence, SFARI, the Templeton World Charitable Fund, the Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research Applied Research Collaboration East of England., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.
Published: 2023

7. Dissecting the 22q13 region to explore the genetic and phenotypic diversity of patients with Phelan-McDermid syndrome

Author: Aline Vitrac, Claire S. Leblond, Thomas Rolland, Freddy Cliquet, Alexandre Mathieu, Anna Maruani, Richard Delorme, Michael Schön, Andreas M. Grabrucker, Conny van Ravenswaaij-Arts, Katy Phelan, Anne-Claude Tabet, Thomas Bourgeron, 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), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Ulm - Ulm University [Ulm, Allemagne], University of Limerick (UL), University of Groningen [Groningen], Florida Hospital Cancer Institute, This study has been supported by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA). ERN-ITHACA is partly co-funded by the Health Programme of the European Union. Funding was also obtained from the European Union's Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N° 825575. This work was also funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris Cité, the Eranet-Neuron (ALTRUISM), the Association Française du Syndrome Phelan-mcDermid and the Association Téhani et les enfants Phelan-McDermid, the GenMed Labex, AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement N° 777394 and the INCEPTION program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the European Union's Horizon 2020 research and innovative program CANDY under grant agreement N° 847818., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 825575,COFUND-EJP, European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Epilepsy, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, Neurodevelopmental disorders, Genetics, Phelan-McDermid syndrome, General Medicine, Brain development, SHANK3, Genetics (clinical)
Abstract: International audience; SHANK3-related Phelan-McDermid syndrome (PMS) is caused by a loss of the distal part of chromosome 22, including SHANK3, or by a pathological SHANK3 variant. There is an important genetic and phenotypic diversity among patients who can present with developmental delay, language impairments, autism, epilepsy, and other symptoms. SHANK3, encoding a synaptic scaffolding protein, is deleted in the majority of patients with PMS and is considered a major gene involved in the neurological impairments of the patients. However, differences in deletion size can influence clinical features, and in some rare cases, deletions at the 22q13 locus in individuals with SHANK3-unrelated PMS do not encompass SHANK3. These individuals with SHANK3-unrelated PMS still display a PMS-like phenotype. This suggests the participation of other 22q13 genes in the pathogenesis of PMS. Here, we review the biological function and potential implication in PMS symptoms of 110 genes located in the 22q13 region, focusing on 35 genes with evidence for association with neurodevelopmental disorders, including 13 genes for epilepsy and 11 genes for microcephaly and/or macrocephaly. Our review is restricted to the 22q13 region, but future large-scale studies using whole genome sequencing and deep-phenotyping are warranted to develop predictive models of clinical trajectories and to target specific medical and educational care for each individual with PMS.
Published: 2023

8. Chapeau UK Biobank! A revolution for integrated research on humans and large-scale data sharing

Author: Bourgeron, Thomas, 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), Académie des Sciences [Paris], and Institut de France
Subjects: Épidémiologie, Population humaine, Epidemiology, Genetics, Biomedical research, Data sharing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], General Medicine, Génétique, Partage de donnée, Biobanque, Biobank, Human population
Abstract: International audience
Published: 2022

9. Neurobiological Correlates of Change in Adaptive Behavior in Autism

Author: Pretzsch, Charlotte, Schäfer, Tim, Lombardo, Michael, Warrier, Varun, Mann, Caroline, Bletsch, Anke, Chatham, Chris, Floris, Dorothea, Tillmann, Julian, Yousaf, Afsheen, Jones, Emily, Charman, Tony, Ambrosino, Sara, Bourgeron, Thomas, Dumas, Guillaume, Loth, Eva, Oakley, Bethany, Buitelaar, Jan, Cliquet, Freddy, Leblond, Claire, Baron-Cohen, Simon, Beckmann, Christian, Banaschewski, Tobias, Durston, Sarah, Freitag, Christine, LEAP Group, Eu-Aims, Murphy, Declan G.M., Ecker, Christine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Frankfurt University Hospital, Goethe-University Frankfurt am Main, University of Trento [Trento], University of Cambridge [UK] (CAM), F. Hoffmann-La Roche [Basel], Universität Zürich [Zürich] = University of Zurich (UZH), University of Vienna [Vienna], Centre for Brain and Cognitive Development [Birkbeck College], Birkbeck College [University of London], Utrecht University [Utrecht], 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), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], University Hospital Mannheim | Universitätsmedizin Mannheim, Heidelberg University, University Medical Center [Utrecht], European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: Psychiatry and Mental health, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Autism Spectrum Disorder, 130 000 Cognitive Neurology & Memory, [SCCO.NEUR]Cognitive science/Neuroscience, Adaptation, Psychological, 220 Statistical Imaging Neuroscience, Humans, Autistic Disorder, Magnetic Resonance Imaging, Follow-Up Studies
Abstract: Objective:Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is associated with significant difficulties in adaptive behavior and variation in clinical outcomes across the life span. Some individuals with ASD improve, whereas others may not change significantly, or regress. Hence, the development of “personalized medicine” approaches is essential. However, this requires an understanding of the biological processes underpinning differences in clinical outcome, at both the individual and subgroup levels, across the lifespan.Methods:The authors conducted a longitudinal follow-up study of 483 individuals (204 with ASD and 279 neurotypical individuals, ages 6–30 years), with assessment time points separated by ∼12–24 months. Data collected included behavioral data (Vineland Adaptive Behavior Scale–II), neuroanatomical data (structural MRI), and genetic data (DNA). Individuals with ASD were grouped into clinically meaningful “increasers,” “no-changers,” and “decreasers” in adaptive behavior. First, the authors compared neuroanatomy between outcome groups. Next, they examined whether deviations from the neurotypical neuroanatomical profile were associated with outcome at the individual level. Finally, they explored the observed neuroanatomical differences’ potential genetic underpinnings.Results:Outcome groups differed in neuroanatomical features (cortical volume and thickness, surface area), including in “social brain” regions previously implicated in ASD. Also, deviations of neuroanatomical features from the neurotypical profile predicted outcome at the individual level. Moreover, neuroanatomical differences were associated with genetic processes relevant to neuroanatomical phenotypes (e.g., synaptic development).Conclusions:This study demonstrates, for the first time, that variation in clinical (adaptive) outcome is associated with both group- and individual-level variation in anatomy of brain regions enriched for genes relevant to ASD. This may facilitate the move toward better targeted/precision medicine approaches.
Published: 2022

10. Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism

Author: Pretzsch, Charlotte, Floris, Dorothea, Schäfer, Tim, Bletsch, Anke, Gurr, Caroline, Lombardo, Michael, Chatham, Chris, Tillmann, Julian, Charman, Tony, Arenella, Martina, Jones, Emily, Ambrosino, Sara, Bourgeron, Thomas, Dumas, Guillaume, Cliquet, Freddy, Leblond, Claire, Loth, Eva, Oakley, Bethany, Buitelaar, Jan, Baron-Cohen, Simon, Beckmann, Christian, Persico, Antonio, Banaschewski, Tobias, Durston, Sarah, Freitag, Christine, Murphy, Declan, Ecker, Christine, King‘s College London, Universität Zürich [Zürich] = University of Zurich (UZH), Radboud University Medical Center [Nijmegen], Goethe-Universität Frankfurt am Main, Istituto Italiano di Tecnologia (IIT), F. Hoffmann-La Roche [Basel], University of London [London], Utrecht University [Utrecht], 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), University of Cambridge [UK] (CAM), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Universität Heidelberg [Heidelberg] = Heidelberg University, The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon-2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. (The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.) Any views expressed are those of the author(s) and not necessarily those of the funders (IHI-JU2). This work was further supported by the European Union Horizon-2020 programme CANDY (Grant Agreement No. 847818). CMF acknowledges support from the European Union and the German Research Association (DFG). DGM acknowledges support from the NIHR Maudsley Biomedical Research Centre., and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: [SCCO.NEUR]Cognitive science/Neuroscience
Abstract: International audience; Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals’ adaptive skills naturally improve or remain stable, while others’ decrease. To pave the way for ‘precision-medicine’ approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6–30 years), with two assessment time points separated by ~12–24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful “Increasers”, “No-changers”, and “Decreasers” in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup’s neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences’ potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.
Published: 2023

11. Consensus recommendations on Epilepsy in Phelan-McDermid syndrome

Author: Irenaeus F.M. de Coo, Sarah Jesse, Thuy-Linh Le, Carlo Sala, Thomas Bourgeron, Maastricht University [Maastricht], Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 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), Istituto di Neuroscienze - Institute of Neuroscience [Milan, Italy] (CNR), Università degli Studi di Milano = University of Milan (UNIMI)-Consiglio Nazionale delle Ricerche [Milano] (CNR), This project has been supported by European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA)., ERN-ITHACA is partly co-funded by the Health Programme of the European Union. This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université Paris Cité, the Eranet-Neuron (ALTRUISM), the GenMed Labex, and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). This project received funding from the European Union's Horizon 2020 research and innovation programmes under CANDY grant agreement N° 847818 and under the EJP RD COFUND-EJP N° 825575.The views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and European Project: 825575,COFUND-EJP
Subjects: Electroencephalogram, Epilepsy, DELETION, Genetics, Phelan-McDermid syndrome, SEIZURES, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], General Medicine, Regression, Genetics (clinical), Brain-MRI
Abstract: International audience; Phelan-McDermid syndrome (PMS) is a 22q13.3 deletion syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities like seizures. The epilepsy manifests itself in a variety of seizure semiologies. Further diagnostics using electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) are important in conjunction with the clinical picture of the seizures to decide whether anticonvulsant therapy is necessary. As part of the development of European consensus guidelines we focussed on the prevalence and semiology of epileptic seizures in PMS associated with a pathogenic variant in the SHANK3 gene or the 22q13 deletion involving SHANK3, in order to then be able to make recommendations regarding diagnosis and therapy.
Published: 2023

12. Tackling hypo and hyper sensory processing heterogeneity in autism: From clinical stratification to genetic pathways

Author: Lefebvre, Aline, Tillmann, Julian, Cliquet, Freddy, Amsellem, Frederique, Maruani, Anna, Leblond, Claire, Beggiato, Anita, Germanaud, David, Amestoy, Anouck, Ly-Le Moal, Myriam, Umbricht, Daniel, Chatham, Christopher, Murtagh, Lorraine, Bouvard, Manuel, Leboyer, Marion, Charman, Tony, Bourgeron, Thomas, Delorme, Richard, Dumas, Guillaume, 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), Psychiatrie de l'enfant et de l'adolescent [Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre hospitalier Fondation Vallée [Gentilly, France] (CHS), Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Centre de Référence Déficiences Intellectuelles de causes rares / Rare Disease Reference Center for Intellectual Disability [CHU Robert Debré, AP-HP], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier Charles Perrens [Bordeaux], Fondation FondaMental [Créteil], Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pôle de Psychiatrie [Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital H. Mondor - A. Chenevier, King‘s College London, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], 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], APHP, Autism Speaks, Autistica and Simons Foundation Autism Research Initiative, DHU protect, European Federation of Pharmaceutical Industries and Associations, European Federation of Pharmaceutical Industries and Associations companies, European Union's Horizon 2020, European Union's Seventh Framework Program, Grant/Award Number: FP7/2007-2013, Fondation a la Recherche Medicale, Fondation de France, Fondation FondaMental, French National Center for Scientific Research, Grant/Award Number: ANR-11-IDEX-0004-02 ANR-10-COHO-10-01 ANR-12-SAMA-0014, Innovative Medicines Initiative 2 Joint Undertaking Grant, Grant/Award Number: 777394, Innovative Medicines Initiative Joint Undertaking, Grant/Award Number: 115300, Innovative Medicines Initiative Joint Undertaking Grant, Institut National de la Santé et de la Recherche Médicale, Institut Pasteur, Grant/Award Number: C07-33, Investissements d'Avenir program, Labex BioPsy, Medical Research Foundation, Roche Institute for Research and Translational Medicine, EU-AIMS LEAP group, ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-12-SAMA-0014,AutoMobil,Encéphalite avec autoanticorps anti-récepteurs synaptiques : un nouveau modèle de troubles psychotiques(2012), ANR-10-COHO-0010,Psy-COH,FondaMental-Cohortes(2010), European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), European Project: AIMS-2-TRIALS, Cliquet, Freddy, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Santé Mentale et Addictions - Encéphalite avec autoanticorps anti-récepteurs synaptiques : un nouveau modèle de troubles psychotiques - - AutoMobil2012 - ANR-12-SAMA-0014 - SAMENTA - VALID, Cohortes - FondaMental-Cohortes - - Psy-COH2010 - ANR-10-COHO-0010 - COHO - VALID, European Autism Interventions - A Multicentre Study for Developing New Medications - EU-AIMS - - EC:FP7:SP1-JTI2012-04-01 - 2017-03-31 - 115300 - VALID, and Autism Innovative Medicine Studies-2-Trials - AIMS-2-TRIALS - INCOMING
Subjects: GABA/glutamatergic pathway, excitation and inhibition balance, General Neuroscience, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, autism, sensory profile, autism spectrum disorder, Neurology (clinical), clinical marker, Genetics (clinical)
Abstract: International audience; As an integral part of autism spectrum symptoms, sensory processing issues including both hypo and hyper sensory sensitivities. These sensory specificities may result from an excitation/inhibition imbalance with a poorly understood of their level of convergence with genetic alterations in GABA-ergic and glutamatergic pathways. In our study, we aimed to characterize the hypo/hyper-sensory profile among autistic individuals. We then explored its link with the burden of deleterious mutations in a subset of individuals with available whole-genome sequencing data. To characterize the hypo/hyper-sensory profile, the differential Short Sensory Profile (dSSP) was defined as a normalized and centralized hypo/hypersensitivity ratio from the Short Sensory Profile (SSP). Including 1136 participants (533 autistic individuals, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP), we observed a statistically significant dSSP mean difference between autistic individuals and controls, driven mostly by a high dSSP variability, with an intermediated profile represented by relatives. Our genetic analysis tended to associate the dSSP and the hyposensitivity with mutations of the GABAergic pathway. The major limitation was the dSSP difficulty to discriminate subjects with a similar quantum of hypo- and hyper-sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0. However, the dSSP could be a relevant clinical score, and combined with additional sensory descriptions, genetics and endophenotypic substrates, will improve the exploration of the underlying neurobiological mechanisms of sensory processing differences in autism spectrum.
Published: 2023

13. Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure

Author: Hollestein, Viola, Poelmans, Geert, Forde, Natalie J, Beckmann, Christian F, Ecker, Christine, Mann, Caroline, Schäfer, Tim, Moessnang, Carolin, Baumeister, Sarah, Banaschewski, Tobias, Bourgeron, Thomas, Loth, Eva, Dell'Acqua, Flavio, Murphy, Declan GM, Puts, Nicolaas A, Tillmann, Julian, Charman, Tony, Jones, Emily JH, Mason, Luke, Ambrosino, Sara, Holt, Rosemary, Bölte, Sven, Buitelaar, Jan K, Naaijen, Jilly, Hollestein, Viola [0000-0002-6326-4172], Poelmans, Geert [0000-0001-7039-6985], Banaschewski, Tobias [0000-0003-4595-1144], Loth, Eva [0000-0001-9458-9167], Murphy, Declan GM [0000-0002-6664-7451], Puts, Nicolaas A [0000-0003-1024-1927], Charman, Tony [0000-0003-1993-6549], Bölte, Sven [0000-0002-4579-4970], Buitelaar, Jan K [0000-0001-8288-7757], Apollo - University of Cambridge Repository, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Goethe-Universität Frankfurt am Main, King‘s College London, Universität Heidelberg [Heidelberg] = Heidelberg University, 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), Sackler Institute of Translational Neurodevelopment [London], F. Hoffmann-La Roche [Basel], University of London [London], Utrecht University [Utrecht], University of Cambridge [UK] (CAM), Karolinska Institutet [Stockholm], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], This work has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI, by the Horizon2020 supported programme CANDY Grant No. 847818 and a Veni grant from the Netherlands organization for scientific research (NWO) under grant number VI.Veni.194.032 awarded to JN. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the authors and not necessarily those of the funders., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and European Project: 101069276,CANDY
Subjects: Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Autism Spectrum Disorder, article, Glutamic Acid, Brain, 692/699/476/1373, Cellular and Molecular Neuroscience, Psychiatry and Mental health, All institutes and research themes of the Radboud University Medical Center, 692/53, 59/57, Humans, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autistic Disorder, 631/378, Transcriptome, gamma-Aminobutyric Acid, Biological Psychiatry
Abstract: Funder: AIMS-2TRIALS/EU-AIMS which receive support from Innovative Medicines Initiative Joint Undertaking grant numbers 115300 and 777394, Funder: Horizon2020 CANDY programme grant number 847818, Funder: Dutch NWO Veni grant grant number VI.Veni.194.032, The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods-combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6-30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.
Published: 2023

14. Processing of social and monetary rewards in autism spectrum disorders

Author: Baumeister, S., Moessnang, C., Bast, N., Hohmann, S., Aggensteiner, P., Kaiser, A., Tillmann, J., Goyard, D., Charman, T., Ambrosino, S., Baron-Cohen, S., Beckmann, C.F., Bölte, S., Bourgeron, T., Rausch, A., Crawley, D., Dell'Acqua, F., Dumas, G., Durston, S., Ecker, C., Floris, D.L., Frouin, V., Hayward, H., Holt, R., Johnson, M.H., Jones, E.J.H., Lai, M.C., Lombardo, M.V., Mason, L., Oakley, B., Oldehinkel, M., Persico, A.M., San José Cáceres, A., Wolfers, T., Loth, E., Murphy, D.G.M., Buitelaar, J.K., Tost, H., Meyer-Lindenberg, A., Banaschewski, T., Brandeis, D., Universität Heidelberg [Heidelberg] = Heidelberg University, Goethe-Universität Frankfurt am Main, King‘s College London, University of Vienna [Vienna], IFR49 - Neurospin - CEA, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Utrecht University [Utrecht], University of Cambridge [UK] (CAM), Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Karolinska Institutet [Stockholm], Stockholm Health Care Services (SLSO), The University of Western Australia (UWA), 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), Universität Zürich [Zürich] = University of Zurich (UZH), University of London [London], University of Toronto, National Taiwan University [Taiwan] (NTU), Istituto Italiano di Tecnologia (IIT), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], This work was supported by EU-AIMS (European Autism Interventions), which received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’ s Seventh Framework Programme (grant FP7/2007-2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and from Autism Speaks. The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: Psychiatry and Mental health, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], fMRI, multisite, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], 220 Statistical Imaging Neuroscience, ADHD symptoms, Autism spectrum disorder, autism traits, reward processing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: BackgroundReward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD.AimsUtilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.MethodFunctional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6–30.6 years of age) and 181 typically developing participants (7.6–30.8 years of age).ResultsAcross social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD.ConclusionsOur results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.
Published: 2023

15. 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

16. Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder

Author: Nico Bast, Clara Moreau, Andre F. Marquand, Varun Warrier, Jan K. Buitelaar, Julian Tillmann, Tim Schaefer, Sarah Baumeister, Andreas G. Chiocchetti, Mariam Zabihi, Christine Ecker, Simon Baron-Cohen, Will Spooren, Flavio Dell’Acqua, Claire Leblond, Carolin Moessnang, Afsheen Yousaf, Christian F. Beckmann, Tobias Banaschewski, Guillaume Dumas, Anke Bletsch, Michael V. Lombardo, Luke Mason, Dorothea L. Floris, Antonio M. Persico, Sara Ambrosino, Declan G. Murphy, Charlotte M. Pretzsch, Emily J.H. Jones, Sven Bölte, Caroline Mann, Sarah Durston, Tony Charman, Christine M. Freitag, Freddy Cliquet, Andreas Meyer-Lindenberg, Thomas Bourgeron, Eva Loth, Nick Puts, Goethe-University Frankfurt am Main, Utrecht University [Utrecht], King‘s College London, University of Trento [Trento], University of Cambridge [UK] (CAM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: genetic structures, Autism Spectrum Disorder, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Neuroimaging, Biology, Gyrus Cinguli, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, mental disorders, Genetics, medicine, Humans, 030304 developmental biology, Cortical Thickness, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Brain, 220 Statistical Imaging Neuroscience, Genomics, medicine.disease, Magnetic Resonance Imaging, Neuroanatomy, Neurodevelopmental Disorders, Psychiatry and Mental health, medicine.anatomical_structure, Autism spectrum disorder, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Neuroscience, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 248865.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
Published: 2022

17. Excessive self-grooming of $Shank3$ mutant mice is associated with gene dysregulation and imbalance between the striosome and matrix compartments in the striatum

Author: Ferhat, Allain-Thibeault, Biton, Anne, Verpy, Elisabeth, Forget, Benoit, de Chaumont, Fabrice, Mueller, Florian, Le Sourd, Anne-Marie, Coqueran, Sabrina, Schmitt, Julien, Rochefort, Christelle, Rondi-Reig, Laure, Leboucher, Aziliz, Boland, Anne, Fin, Bertrand, Deleuze, Jean François, Boeckers, Tobias, Ey, Elodie, Bourgeron, Thomas, 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), Columbia University Medical Center (CUMC), Columbia University [New York], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Modélisation - Imaging and Modeling, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CeZaMe - Cervelet, navigation et mémoire = Memory, Navigation and Aging (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Universität Ulm - Ulm University [Ulm, Allemagne], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-10-LABX-BioPsy, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Ey, Elodie, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, and Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID
Subjects: [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: Autism spectrum disorders (ASD) are characterised by atypical social communication and stereotyped behaviours. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with ASD and intellectual disability (ID), but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behaviour of Shank3 mutant mice deleted for exon 11 ( Shank3 $^{Δ11/Δ11}$ ) from three to twelve months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and atypical socio-sexual interaction compared to wild-type littermates. We then used RNAseq on four brain regions of the same animals to identify differentially expressed genes (DEG). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g. Grm2 , Dlgap1 ), G-protein-signalling pathways (e.g. Gnal , Prkcg1 , and Camk2g ), as well as excitation/inhibition balance (e.g. Gad2 ). Downregulated and upregulated genes were respectively enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN). Moreover, expression of DEGs reported as striosome markers within the striatum ( Cnr1 , Gnal1 , Gad2 , and Drd4 ) were positively correlated with excessive self-grooming. Finally, we showed that the striosome compartment of Shank3 Shank3 $^{Δ11/Δ11}$ mice was enlarged and displayed higher expression of GAD65 compared to wild-type mice. Altogether, these results shed light on a possible role of the striosomes/matrix imbalance in excessive self-grooming in Shank3Shank3 $^{Δ11/Δ11}$ mice. Such striatal alterations could be present in a subgroup of patients with ASD and ID and could open the way to new therapeutic approaches.
Published: 2022

18. A 16p11.2 deletion mouse model displays quantitatively and qualitatively different behaviours in sociability and social novelty over short- and long-term observation

Author: Anna Rusu, Claire Chevalier, Fabrice de Chaumont, Valérie Nalesso, Véronique Brault, Yann Hérault, Elodie Ey, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: BackgroundAutism spectrum disorders affect more than one percent of the population, impairing social communication and increasing stereotyped behaviours. A micro-deletion of the 16p11.2 BP4-BP5 chromosomic region has been identified in one percent of patients also displaying intellectual disabilities. In mouse models generated to understand the mechanisms of this deletion, learning and memory deficits were pervasive in most genetic backgrounds, while social communication deficits were only detected in some models. Based on previous study (Arbogast et al. 2016 PLoS genetics), we selected the mouse model of 16p11.2 deletion on a hybrid C57BL/6NxC3B genetic background to itemize the social deficits. We examined whether behavioural deficits observed in short observation periods were representative of the phenotype displayed by the same mice over long-term monitoring. We recorded the individual and social behaviours of 16p11.2 Del/+ mice and their wild-type littermates from both sexes in short-term (15 min) and long-term (over two and three consecutive nights) social interactions of familiar mixed-genotype quartets of males and of females, and of same-genotype unfamiliar female pairs.ResultsWe observed that Del/+ mice of both sexes increased significantly their activity compared to wild-type littermates only over long-term monitoring. In the social domain, Del/+ mice of both sexes displayed only limited impairments over short-term monitoring, and more visible deficits over long-term monitoring. When recorded in quartets of familiar individuals, social impairments were stronger in males than in females. In pairs, significant perturbations of the organisation of the social communication and behaviours in Del/+ females appeared mostly over the long-term.ConclusionsAltogether, this suggests that social and contextual variations affect the phenotype of the 16p11.2 Del/+ mice differently in the activity and the social domains. The social behaviour was also differently affected between the two sexes. These findings confirm the importance of testing models both in short- and long-term conditions to provide a comprehensive view of their phenotype that will be more robust for pre-clinical targeted therapeutic trials.
Published: 2022

19. Humanized Chimeric Mouse Models to Study Human Neural Development and Pathogenesis of Brain Diseases

Author: Camille Thiberge, Maria Llach Pou, Aline Vitrac, Uwe Maskos, Isabelle Cloëz-Tayarani, Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), 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), The 'Fondation Recherche Alzheimer' provides the funding for CT’s PhD. The Pasteur-Paris University (PPU) international doctoral program provides the funding for MLP’s PhD. The French Ministry of Education and the LabEx BioPsy provided the funding for AV’s PhD. Other funding for this study were provided by grants from the French National Research Agency ANR (ANR-17-NEU3-0004, IPS BRAIN), from ERA-NET NEURON (iPSC & Brain), and from the 'France Alzheimer' foundation. We gratefully acknowledge the UtechS Photonic Bioimaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10-INSB-04, Investments for the future)., The authors are thankful to Dr. Alexandra Benchoua who performed the initial iPSC reprogramming, ANR-17-NEU3-0004,iPS_BRAIN,A functional dissection of human nicotinic receptor polymorphisms linked to addiction and schizophrenia(2017), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Subjects: chimeric mouse models, neurodevelopment, Xenografting, induced pluripotent stem cells, neurodevelopmental disorders, in utero transplant, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], human stem cells, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: International audience; The development of humanized neural chimeric mouse models consists in grafting human neuronal progenitor cells (NPC) or differentiated neurons derived from induced pluripotent stem cells (iPSC) into the mouse brain at different timepoints. As the main features of cortical networks and their alterations during brain development cannot be reproduced in vitro, these in vivo models have been used to investigate the mechanisms by which reprogrammed human neurons and non-neuronal cells integrate and migrate into the mouse brain at early stages of brain development and display functional activities several months after their grafting. Here, we describe the neonatal grafting technique of human NPC which we use in our laboratory. We also present a new method based on the grafting of human NPC into the brain of mouse embryos, in utero. A third method consists in the stereotaxic grafting of human NPC into selected brain regions of adult mice. The iPSC technology combined with the use of chimeric mouse models offers numerous possibilities to study human neural development within wellcontrolled and defined temporal windows and to model neuropathological disorders.
Published: 2022

20. Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Author: Eising, E., Mirza-Schreiber, N., Zeeuw, E.L. de, Wang, C.A., Truong, D.T., Allegrini, A.G., Shapland, C.Y., Zhu, G., Wigg, K.G., Gerritse, M.L., Molz, B., Alagöz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., Donkelaar, M.M.J. van, Liao, Z., Jansen, P.R., Andlauer, T.F.M., Bates, T.C., Bernard, M., Blokland, K., Bonte, M., Børglum, A.D., Bourgeron, T., Brandeis, D., Ceroni, F., Csépe, V., Dale, P.S., Jong, P.F. de, DeFries, J.C., Démonet, J.F., Demontis, D., Feng, Yu, Gordon, S.D.S., Guger, S.L., Hayiou-Thomas, M.E., Hernández-Cabrera, J.A., Hottenga, J.J., Hulme, C., Kere, J., Kerr, E.N., Koomar, T., Landerl, K., Leonard, G.T., Lovett, M.W., Lyytinen, H., Martin, N.G., Martinelli, A., Maurer, U., Michaelson, J.J., Moll, K., Monaco, A.P., Morgan, A.T., Nöthen, M.M., Pausova, Z., Pennell, C.E., Pennington, B.F., Price, K.M., Rajagopal, V.M., Ramus, F., Richer, L., Simpson, N.H., Smith, S.D., Snowling, M.J., Stein, J., Strug, L.J., Talcott, J.B., Tiemeier, H., Schroeff, M.P. van der, Verhoef, E., Watkins, K.E., Wilkinson, M., Wright, M.J., Barr, C.L., Boomsma, D.I., Carreiras, M., Franken, M.J., Gruen, J.R., Luciano, M., Müller-Myhsok, B., Newbury, D.F., Olson, R.K., Paracchini, S., Paus, T., Plomin, R., Reilly, S., Schulte-Körne, G., Tomblin, J.B., Bergen, E. van, Whitehouse, A.J.O., Willcutt, E.G., Pourcain, B. St, Francks, C., Fisher, S.E., St Pourcain, B., 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), Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Human genetics, APH - Aging & Later Life, APH - Mental Health, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Methodology, LEARN! - Educational neuroscience, learning and development, Child and Adolescent Psychiatry / Psychology, Otorhinolaryngology and Head and Neck Surgery, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Research Programs Unit, University of Helsinki, Language, RS: FPN CN 7, The Royal Society, University of St Andrews. Cellular Medicine Division, University of St Andrews. School of Medicine, University of St Andrews. Centre for Biophotonics, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. Institute of Behavioural and Neural Sciences, and University of St Andrews. St Andrews Bioinformatics Unit
Subjects: Neuroinformatics, Adult, kieli ja kielet, Adolescent, Individuality, QH426 Genetics, Polymorphism, Single Nucleotide, lukeminen, Language in Interaction, Young Adult, SDG 3 - Good Health and Well-being, RA0421, reading, RA0421 Public health. Hygiene. Preventive Medicine, Humans, Speech, study, Polymorphism, Reading j, Preschool, Child, QH426, perinnöllisyys, Genome-wide Association Study, Language, Meta-analysis, Reading, MCC, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genome-wide association study, language, Multidisciplinary, meta-analyysi, 1184 Genetics, developmental biology, physiology, kielitaito, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, DAS, Single Nucleotide, meta-analysis, Genetic Loci, Child, Preschool, Genome-Wide Association Study, perimä, lukutaito, genome-wide association, SDG 4 - Quality Education
Abstract: Published August 23, 2022 The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 1028) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Université de Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigación through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocognition, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children’s Hospital of Philadelphia, and a donation from Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark.
Published: 2022

21. Structural and functional brain alterations revealed by neuroimaging in CNV carriers

Author: Christopher R.K. Ching, Carrie E. Bearden, Clara Moreau, Sébastien Jacquemont, Kuldeep Kumar, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre Hospitalier Universitaire Sainte Justine (CHU Sainte Justine), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Keck School of Medicine [Los Angeles], University of Southern California (USC), Semel Institute for Neuroscience and Human Behavior [Los Angeles, Ca], University of California [Los Angeles] (UCLA), University of California-University of California, This work 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, and the National Institute of Mental Health (grants R01MH085953, R21MH116473, and 9U01MH119736-02).Dr Jacquemont is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. Kuldeep Kumar was supported by The Institute of Data Valorization (IVADO) Postdoctoral Fellowship program, through the Canada First Research Excellence Fund. CRKC was supported by NIAT32AG058507 and U54EB020403 from the Big Data to Knowledge (BD2K) Program., We wish to thank Sophia Thomopoulos for her assistance with accessing effect size data from the published ENIGMA studies for Figure 2. We also thank the ENIGMA 22q11.2 Deletion Syndrome Working Group (http://enigma.ini.usc.edu/ongoing/enigma-22q-working-group/) and CNV Working Group members (http://enigma.ini.usc.edu/ongoing/enigma-cnv/) for their contributions to these large-scale collaborative studies., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Sainte Justine [Montréal], and University of California (UC)-University of California (UC)
Subjects: DNA Copy Number Variations, Endophenotypes, Population, Neuroimaging, Genomics, Computational biology, Biology, Article, 03 medical and health sciences, Functional brain, 0302 clinical medicine, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Copy-number variation, Aetiology, education, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, education.field_of_study, Mental Disorders, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, Neurosciences, Brain, Brain Disorders, 3. Good health, Mental Health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Endophenotype, Neurological, Patient Safety, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: International audience; Copy Number Variants (CNVs) are associated with elevated rates of neuropsychiatric disorders. A 'genetics-first' approach, involving the CNV effects on the brain, irrespective of clinical symptomatology, allows investigation of mechanisms underlying neuropsychiatric disorders in the general population. Recent years have seen an increasing number of larger multisite neuroimaging studies investigating the effect of CNVs on structural and functional brain endophenotypes. Alterations overlap with those found in idiopathic psychiatric conditions but effect sizes are twofold to fivefold larger. Here we review new CNV-associated structural and functional brain alterations and outline the future of neuroimaging genomics research, with particular emphasis on developing new resources for the study of high-risk CNVs and rare genomic variants.
Published: 2021

22. 10q26 deletion syndrome: a French cohort study

Author: Thorn, Hugo, Odent, Sylvie, Levy, Jonathan, Tabet, Anne-Claude, Thevenon, Julien, Caignec, Cedric Le, Schaefer, Elise, Frebourg, Thierry, Schluth-Bolard, Caroline, Plutino, Morgane, Chehadeh, Salima El, Philippe, Anais, Scheidecker, Sophie, Calmels, Nadege, Schalk, Audrey, Goldenberg, Alice, Guerot, Anne-Marie, Meur, Nathalie Le, Cassinari, Kevin, Ruaud, Lyse, Rachid, Myriam, Januel, Louis, Bonnet-Dupeyron, Marie-Noëlle, Carneiro, Maryline, Bieth, Eric, Plaisancie, Julie, Coutton, Charles, Harbuz, Radu, Dieterich, Klaus, Nadeau, Gwenaël, Vieville, Gaelle, Fradin, Melanie, Poirsier, Celine, Spodenkiewicz, Marta, Landais, Emilie, Doco-Fenzy, Martine, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), CHU Grenoble, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Rouen, Normandie Université (NU), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier de Valence, Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Métropole Savoie [Chambéry], CHU Pontchaillou [Rennes], SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA), Wiener Medizinische Akademie GmbH, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), CHU Toulouse [Toulouse], and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; 10q26 deletion syndrome (OMIM #609625) is a rare autosomal dominant genetic disorder with about 100 patients reported. Most cases are sporadic. Global development delay, short stature, microcephaly and typical facial appearance with triangular face, large forehead, low-set malformed ears, hypertelorism, prominent nose and a thin vermilion of the upper lip constitute the main clinical features. The clinical spectrum is very heterogeneous and neurobehavioral manifestations, deafness, limb malformations, cardiac and urogenital abnormalities can be associated. Thus, patients with 10q26 chromosomal deletion need multidisciplinary management strategies from birth. One of the main reasons for this heterogeneity is the variety of 10qter region chromosomal deletions summarized into the “10q26 deletion syndrome”. Various studies proposed critical regions to explain the main phenotype (Yatzenko et al., 2009; Choucair et al., 2015; Lin S et al., 2016) or more specific features (Vera-Carbonell et al., 2015; Choucair et al., 2015). In addition, these studies proposed about 20 genes of interest such as DOCK1 and FGFR2 to explain the different clinical features observed. We report a French ACLF cohort of 35 patients from 9 centers presenting 10q26 complete or partial deletions (size: 64kb to 12.5Mb), complex chromosomal rearrangement and derivative chromosomes diagnosed using DNA-array, to bring a further insight of the genotype/phenotype correlation.
Published: 2022

23. Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis

Author: Garcés, Pilar, Baumeister, Sarah, Mason, Luke, Chatham, Christopher, Holiga, Stefan, Dukart, Juergen, Jones, Emily, Banaschewski, Tobias, Baron-Cohen, Simon, Bölte, Sven, Buitelaar, Jan, Durston, Sarah, Oranje, Bob, Persico, Antonio, Beckmann, Christian, Bougeron, Thomas, Dell’acqua, Flavio, Ecker, Christine, Moessnang, Carolin, Charman, Tony, Tillmann, Julian, Murphy, Declan, Johnson, Mark, Loth, Eva, Brandeis, Daniel, Hipp, Joerg, Ahmad, Jumana, Ambrosino, Sara, Auyeung, Bonnie, Bourgeron, Thomas, Bours, Carsten, Brammer, Michael, Brogna, Claudia, de Bruijn, Yvette, Chakrabarti, Bhismadev, Cornelissen, Ineke, Crawley, Daisy, Dumas, Guillaume, Faulkner, Jessica, Frouin, Vincent, Goyard, David, Ham, Lindsay, Hayward, Hannah, Holt, Rosemary, Kundu, Prantik, Lai, Meng-Chuan, Ardhuy, Xavier Liogier D’, Lombardo, Michael, Lythgoe, David, Mandl, René, Marquand, Andre, Mennes, Maarten, Meyer-Lindenberg, Andreas, Mueller, Nico, Oakley, Bethany, O’dwyer, Laurence, Oldehinkel, Marianne, Pandina, Gahan, Ruggeri, Barbara, Ruigrok, Amber, Sabet, Jessica, Sacco, Roberto, Cáceres, Antonia San José, Simonoff, Emily, Spooren, Will, Toro, Roberto, Tost, Heike, Waldman, Jack, Williams, Steve, Wooldridge, Caroline, Zwiers, Marcel, Leap Group, The Eu-Aims, Garcés, Pilar [0000-0003-4989-0123], Apollo - University of Cambridge Repository, Roche Innovation Center [Basel, Switzerland], Heidelberg University, University Hospital Mannheim | Universitätsmedizin Mannheim, University of London [London], Institute of Neuroscience and Medicine, Brain and Behaviour [Jülich, Germany] (INM-7), Jülich Research Centre, Autism Research Centre [Cambridge, Royaume-Uni], University of Cambridge [UK] (CAM), Centre for Psychiatry Research [Stockholm], Karolinska Institutet [Stockholm], Curtin University [Perth], Planning and Transport Research Centre (PATREC), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University Medical Center [Utrecht], Università degli Studi di Messina = University of Messina (UniMe), 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), King‘s College London, Goethe-University Frankfurt am Main, Central Institute of Mental Health [Mannheim], This work was supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (grant FP7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions and from Autism Speaks. AIMS-2-TRIALS is funded by the Innovative Medicines Initiative 2 Joint Undertaking (IMI 2 JU) under grant agreement no. 777394. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program, EFPIA, Autism Speaks, Autistica, and SFARI. PG was supported by the Roche Postdoctoral Fellowship (RPF) program., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and University of Zurich
Subjects: Adult, Adolescent, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Autism spectrum disorder, EEG, Resting state, Power spectrum, Functional connectivity, 610 Medicine & health, 1309 Developmental Biology, 2806 Developmental Neuroscience, 2738 Psychiatry and Mental Health, Developmental Neuroscience, 130 000 Cognitive Neurology & Memory, 1312 Molecular Biology, Humans, ddc:610, 10064 Neuroscience Center Zurich, Autistic Disorder, Child, Molecular Biology, Brain Mapping, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Research, 220 Statistical Imaging Neuroscience, Brain, Reproducibility of Results, Electroencephalography, 10058 Department of Child and Adolescent Psychiatry, Magnetic Resonance Imaging, Psychiatry and Mental health, Cross-Sectional Studies, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Developmental Biology
Abstract: Background Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. Methods We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2–32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants’ MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%–30% split). Results In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52–0.62, specificity 0.59–0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. Limitations The statistical power to detect weak effects—of the magnitude of those found in the training dataset—in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset’s effects. Conclusions This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects., Molecular Autism, 13
Published: 2022

24. Sub-diagnostic effects of genetic variants associated with autism

Author: Thomas Rolland, Freddy Cliquet, Richard J.L. Anney, Clara Moreau, Nicolas Traut, Alexandre Mathieu, Guillaume Huguet, Jinjie Duan, Varun Warrier, Swan Portalier, Louise Dry, Claire S. Leblond, Elise Douard, Frédérique Amsellem, Simon Malesys, Anna Maruani, Roberto Toro, Anders D. Børglum, Jakob Grove, Simon Baron-Cohen, Alan Packer, Wendy K. Chung, Sébastien Jacquemont, Richard Delorme, Thomas Bourgeron, 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), Cardiff University, Centre de Recherches Interdisciplinaires (CRI), Université Paris Cité (UPCité), Université de Montréal (UdeM), 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], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), Department of Biomedicine, Aarhus University, Autism Research Centre [Cambridge, Royaume-Uni], University of Cambridge [UK] (CAM), Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Bioinformatics Research Centre, Aarhus University, Simons Foundation, Columbia University Medical Center (CUMC), Columbia University [New York], This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Eranet-Neuron (ALTRUISM), the GenMed Labex, AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the European Union’s Horizon 2020 research and innovative program CANDY under grant agreement No 847818., and ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016)
Subjects: Genetics, 0303 health sciences, education.field_of_study, media_common.quotation_subject, Population, Genetic variants, Heterozygote advantage, Biology, medicine.disease, Penetrance, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], mental disorders, medicine, Autism, Psychological resilience, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract: While over a hundred genes are significantly associated with autism, little is known about the prevalence of variants affecting them in the general population. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Using data from more than 13,000 autistic individuals and 210,000 undiagnosed individuals, we provide a gene-level map of the odds ratio for autism associated to rare loss-of-function (LoF) variants in 185 genes robustly associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the phenotype of undiagnosed individuals heterozygous for such variants and show that they exhibit a decrease in fluid intelligence, qualification level and income, and an increase in material deprivation. These effects were larger for LoFs in autism-associated genes than in other LoF-intolerant genes and appeared largely independent of sex and polygenic scores for autism. Using brain imaging data from 21,049 UK-Biobank individuals, we provide evidence for smaller cortical surface area and volume among carriers of LoFs in genes with high odds ratios for autism. Our gene-level map is a key resource to distinguish genes with high and low odds ratio for autism, and highlights the importance of including quantitative data on both diagnosed and undiagnosed individuals to better delineate the effect of genetic variants beyond the categorical diagnosis. Data are available at https://genetrek.pasteur.fr/.
Published: 2022

25. Brain charts for the human lifespan

Author: Armin Raznahan, Eric Courchesne, Andrea Parolin Jackowski, Kamen A. Tsvetanov, Cameron T. Ellis, R.C. Gur, Bin Bae J, Park Mtm, Pedro A. Valdes-Sosa, Simon N. Vandekar, Jacob W. Vogel, Juan Zhou, Machteld Marcelis, Kiho Im, Patricia Ellen Grant, Minhui Ouyang, Blesa Cabez M, Michael V. Lombardo, Sarah E. Morgan, James P. Boardman, Adamson C, Calhoun Vd, Delarue M, James H. Cole, Pichet Binette A, Roberto Toro, David H. Rowitch, Nynke A. Groenewold, Kevin M. Anderson, David T.W. Jones, Michael Schöll, Wang Ys, Aiden Corvin, R.E. Gur, Damien A. Fair, Gareth Ball, Herma Lina Schaare, Andrew Zalesky, Evdokia Anagnostou, Michael J. Meaney, Taki Y, Gareth J. Sullivan, Warrier, Petra E. Vértes, Chixiang Chen, Lisa T. Eyler, Wei Liao, Tomáš Paus, Jeremy A. Elman, Phillip McGuire, Hisham Ziauddeen, William S. Kremen, Etienne Vachon-Presseau, E.T. Bullmore, Christophe Tzourio, White, Hammill Cf, Mothersill D, Richard N. Henson, Jiang Qiu, Duncan E. Astle, Fabrice Crivello, Paul C. Fletcher, Chertavian C, Kim K, Jennifer Crosbie, Russell Schachar, Gabriel A. Devenyi, Manfred G. Kitzbichler, Tianye Jia, Trey Hedden, Sang Jae Lee, Ross D. Markello, Silke Kern, Ian M. Goodyer, Keith A. Johnson, Frauke Beyer, Bernard Mazoyer, A. Heinz, Sylvane Desrivières, Rosenberg, Gary Donohoe, Ong Mq, Alexander D. Edwards, Dan J. Stein, Nenad Medic, Zuo Xn, Travis T. Mallard, Peter Fonagy, Lindsay W. Victoria, Ingmar Skoog, Avram J. Holmes, Jason P. Lerch, Jed T. Elison, Jianfu Li, John H. Gilmore, Rosemary Holt, Caitlin K. Rollins, Carol E. Franz, Pedro Mario Pan, Saashi A Bedford, Yang N, Jonathan C Ipser, Richard A. I. Bethlehem, Tuulari Jj, Stolicyn A, Hua Huang, Bratislav Misic, Conor Liston, Ayub M, Lisa Ronan, Yeo Bt, Sophie Adler, Charles J. Lynch, Faith M. Gunning, Konrad Wagstyl, M. Mallar Chakravarty, John Suckling, Theodore D. Satterthwaite, Bharath Holla, Yap Seng Chong, Jinglei Lv, Jakob Seidlitz, Niall J Bourke, Xinlei Qian, Simon Baron-Cohen, Cynthia M. Ortinau, Deirel Paz Linares, Thyreau B, René S. Kahn, Aaron P. Schultz, Vanessa Cropley, Eric Westman, Mitchell Valdés-Sosa, Rik Ossenkoppele, André Zugman, Hasse Karlsson, Sylvia Villeneuve, Katja Heuer, Di Biase Ma, Margaret L. Westwater, Sofie L. Valk, David J. Sharp, Brigitte Landeau, Matthew Borzage, Kirsten A. Donald, Timothy Rittman, Richard Beare, Giovanni Abrahão Salum, Gunter Schumann, Ryuta Kawashima, Romero-Garcia R, John Blangero, Yun Hj, Russel T. Shinohara, Nicolas Crossley, Simon K. Warfield, Karen Pierce, George S. Alexopoulos, Katharine Dunlop, David C. Glahn, Francois Lalonde, Anqi Qiu, Lana Vasung, Gaël Chételat, Lídice Galán-García, Clifford R. Jack, Reisa A. Sperling, Anna Zettergren, Elizabeth Kelley, Arno Villringer, Andrea Mechelli, Benegal, Aaron Alexander-Bloch, Nicholas B. Turk-Browne, van Amelsvoort T, John D. Lewis, Heather C. Whalley, A. V. Witte, Zdenka Pausova, Joel T. Nigg, Heather J. Zar, Raymond J. Dolan, Christopher D. Smyser, Jay N. Giedd, Lena Palaniyappan, Ali Gholipour, Areces-Gonzalez A, Peter B. Jones, Jacqueline Hoare, Oskar Hansson, Linnea Karlsson, C Pantelis, Paly L, Bonnie Auyeung, Jorge Bosch-Bayard, Bethlehem, Richard [0000-0002-0714-0685], White, Simon [0000-0001-8642-7037], Astle, Duncan [0000-0002-7042-5392], Baron-Cohen, Simon [0000-0001-9217-2544], Henson, Rik [0000-0002-0712-2639], Jones, Peter [0000-0002-0387-880X], Kitzbichler, Manfred [0000-0002-4494-0753], Rittman, Timothy [0000-0003-1063-6937], Rowitch, David [0000-0002-0079-0060], Tsvetanov, Kamen A. [0000-0002-3178-6363], Westwater-Wozniak, Margaret [0000-0002-2918-0979], Ziauddeen, Hisham [0000-0003-4044-1719], Apollo - University of Cambridge Repository, British Academy, Autism Research Trust, National Institute of Mental Health (US), UK Research and Innovation, Medical Research Council (UK), National Institute for Health and Care Research (US), Wellcome Trust, University of Cambridge, Cambridge Biomedical Research Centre, University of Cambridge [UK] (CAM), University of Pennsylvania, Yale University [New Haven], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Neuroscience - Department of Neuroscience, Centre de Recherche Interdisciplinaire / Center for Research and Interdisciplinarity [Paris, France] (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), Neurology, Amsterdam Neuroscience - Neurodegeneration, 3R-BRAIN, AIBL, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Repository Without Borders Investigators, CALM Team, Cam-CAN, CCNP, COBRE, cVEDA, ENIGMA Developmental Brain Age Working Group, Developing Human Connectome Project, FinnBrain, Harvard Aging Brain Study, IMAGEN, KNE96, The Mayo Clinic Study of Aging, NSPN, POND, The PREVENT-AD Research Group, VETSA, [Bethlehem, R. A. I.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Auyeung, B.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Baron-Cohen, S.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Bedford, S. A.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Holt, R.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Lombardo, M. V.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Bethlehem, R. A. I.] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Cambridge, England, [Kitzbichler, M. G.] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Cambridge, England, [Seidlitz, J.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Vogel, J. W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Gur, R. E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Gur, R. C.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Jackowski, A. P.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Satterthwaite, T. D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Alexander-Bloch, A. F.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Seidlitz, J.] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, Philadelphia, PA 19104 USA, [Alexander-Bloch, A. F.] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, Philadelphia, PA 19104 USA, [Seidlitz, J.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Chertavian, C.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Gur, R. E.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Gur, R. C.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Alexander-Bloch, A. F.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [White, S. R.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Goodyer, I. M.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Henson, R. N.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Jones, P. B.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Kitzbichler, M. G.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Medic, N.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Morgan, S. E.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Romero-Garcia, R.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Ronan, L.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Suckling, J.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Vertes, P. E.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Warrier, V.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Westwater, M. L.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Ziauddeen, H.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Bullmore, E. T.] Univ Cambridge, Dept Psychiat, Cambridge, England, [White, S. R.] Univ Cambridge, MRC Biostat Unit, Cambridge, England, [Vogel, J. W.] Univ Penn, Lifespan Informat & Neuroimaging Ctr, Philadelphia, PA 19104 USA, [Satterthwaite, T. D.] Univ Penn, Lifespan Informat & Neuroimaging Ctr, Philadelphia, PA 19104 USA, [Anderson, K. M.] Yale Univ, Dept Psychol, New Haven, CT USA, [Ellis, C. T.] Yale Univ, Dept Psychol, New Haven, CT USA, [Turk-Browne, N. B.] Yale Univ, Dept Psychol, New Haven, CT USA, [Adamson, C.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Ball, G.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Beare, R.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Jackowski, A. P.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Adamson, C.] Monash Univ, Dept Med, Melbourne, Vic, Australia, [Beare, R.] Monash Univ, Dept Med, Melbourne, Vic, Australia, [Adler, S.] UCL Great Ormond St Inst Child Hlth, London, England, [Alexopoulos, G. S.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Anagnostou, E.] Univ Toronto, Dept Pediat, Toronto, ON, Canada, [Anagnostou, E.] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada, [Pierce, K.] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada, [Areces-Gonzalez, A.] Univ Elect Sci & Technol China, MOE Key Lab NeuroInformat, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Paz-Linares, D.] Univ Elect Sci & Technol China, MOE Key Lab NeuroInformat, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Areces-Gonzalez, A.] Univ Pinar del Rio Hermanos Saiz Montes de Oca, Pinar Del Rio, Cuba, [Astle, D. E.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Henson, R. N.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Whalley, H. C.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Auyeung, B.] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, Edinburgh, Midlothian, Scotland, [Pausova, Z.] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, Edinburgh, Midlothian, Scotland, [Ayub, M.] Queens Univ, Dept Psychiat, Ctr Neurosci Studies, Kingston, ON, Canada, [Ayub, M.] UCL, Mental Hlth Neurosci Res Dept, Div Psychiat, London, England, [Bae, J.] Seoul Natl Univ, Bundang Hosp, Dept Neuropsychiat, Seongnam, South Korea, [Ball, G.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia, [Baron-Cohen, S.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge Lifetime Asperger Syndrome Serv CLASS, Cambridge, England, [Benegal, V.] Natl Inst Mental Hlth & Neurosci NIMHANS, Ctr Addict Med, Bengaluru, India, [Beyer, F.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Villringer, A.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Witte, A. V.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Blangero, J.] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Dept Human Genet, Edinburg, TX USA, [Blesa Cabez, M.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Boardman, J. P.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Sullivan, G.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Borzage, M.] Univ Southern Calif, Childrens Hosp Los Angeles, Keck Sch Med, Fetal & Neonatal Inst,Div Neonatol,Dept Pediat, Los Angeles, CA 90007 USA, [Bosch-Bayard, J. F.] Montreal Neurol Inst, Ludmer Ctr Neuroinformat & Mental Hlth, McGill Ctr Integrat Neurosci, Montreal, PQ, Canada, [Bosch-Bayard, J. F.] McGill Univ, Montreal, PQ, Canada, [Chakravarty, M. M.] McGill Univ, Montreal, PQ, Canada, [Bourke, N.] Imperial Coll London, Dept Brain Sci, London, England, [Sharp, D.] Imperial Coll London, Dept Brain Sci, London, England, [Alexander-Bloch, A. F.] Imperial Coll London, Dept Brain Sci, London, England, [Bourke, N.] Dementia Res Inst, Care Res & Technol Ctr, London, England, [Calhoun, V. D.] Georgia State Univ, Triinst Ctr Translat Res Neuroimaging & Data Sci, Georgia Inst Technol, Atlanta, GA 30303 USA, [Calhoun, V. D.] Emory Univ, Atlanta, GA 30322 USA, [Chakravarty, M. M.] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Comp Brain Anat CoBrA Lab, Montreal, PQ, Canada, [Chen, C.] Univ Penn, Penn Stat Imaging & Visualizat Ctr, Dept Biostat Epidemiol & Informat, Perelman Sch Med, Philadelphia, PA 19104 USA, [Shinohara, R. T.] Univ Penn, Penn Stat Imaging & Visualizat Ctr, Dept Biostat Epidemiol & Informat, Perelman Sch Med, Philadelphia, PA 19104 USA, [Chetelat, G.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Delarue, M.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Landeau, B.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Paly, L.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Chong, Y. S.] Agcy Sci Technol & Res, Singapore Inst Clin Sci, Singapore, Singapore, [Chong, Y. S.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynaecol, Singapore, Singapore, [Cole, J. H.] UCL, Ctr Med Image Comp CMIC, London, England, [Cole, J. 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E.] Harvard Med Sch, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston Childrens Hosp, Div Newborn Med & Neuroradiol, Boston, MA 02115 USA, [Groenewold, N. A.] Univ Cape Town, SA MRC Unit Child & Adolescent Hlth, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa, [Zar, H. J.] Univ Cape Town, SA MRC Unit Child & Adolescent Hlth, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa, [Gunning, F. M.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Victoria, L. W.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Hammill, C. F.] Mouse Imaging Ctr, Toronto, ON, Canada, [Hansson, O.] Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Malmo, Sweden, [Hansson, O.] Skane Univ Hosp, Memory Clin, Malmo, Sweden, [Hedden, T.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA, [Hedden, T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Boston, MA 02115 USA, [Heinz, A.] Charite Univ Med Berlin, Charite Campus Mitte, Berlin, Germany, [Heinz, A.] Free Univ Berlin, Charite Campus Mitte, Berlin, Germany, [Heinz, A.] Humboldt Univ, Dept Psychiat & Psychotherapy, Charite Campus Mitte, Berlin, Germany, [Heuer, K.] Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, Leipzig, Germany, [Heuer, K.] Univ Paris, Paris, France, [Toro, R.] Univ Paris, Paris, France, [Hoare, J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa, [Holla, B.] NIMHANS, Dept Integrat Med, Bengaluru, India, [Holla, B.] NIMHANS, Dept Psychiat, Accelerator Program Discovery Brain Disorders Usi, Bengaluru, India, [Holmes, A. J.] Yale Univ, Dept Psychol, New Haven, CT USA, [Villeneuve, S.] Yale Univ, Dept Psychol, New Haven, CT USA, [Holmes, A. J.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA, [Villeneuve, S.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA, [Huang, H.] Childrens Hosp Philadelphia, Radiol Res, Philadelphia, PA 19104 USA, [Ouyang, M.] Childrens Hosp Philadelphia, Radiol Res, Philadelphia, PA 19104 USA, [Huang, H.] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA, [Ipser, J.] Univ Cape Town, Dept Psychiat & Mental Hlth, Clin Neurosci Inst, Cape Town, South Africa, [Jack, C. R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA, [Jones, D. T.] Mayo Clin, Dept Radiol, Rochester, MN USA, Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil, [Jackowski, A. P.] Natl Inst Dev Psychiat, Beijing, Peoples R China, [Jia, T.] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China, [Jia, T.] Fudan Univ, Minist Educ, Key Lab Computat Neurosci & Brain Inspired Intell, Shanghai, Peoples R China, [Jia, T.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Precis Med PONS, SGDP Ctr, London, England, [Johnson, K. A.] Massachusetts Gen Hosp, Dept Neurol, Harvard Aging Brain Study, Boston, MA 02114 USA, [Schultz, A. P.] Massachusetts Gen Hosp, Dept Neurol, Harvard Aging Brain Study, Boston, MA 02114 USA, [Sperling, R. A.] Massachusetts Gen Hosp, Dept Neurol, Harvard Aging Brain Study, Boston, MA 02114 USA, [Johnson, K. A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, 75 Francis St, Boston, MA 02115 USA, [Sperling, R. A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, 75 Francis St, Boston, MA 02115 USA, [Johnson, K. A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA, [Jones, D. T.] Mayo Clin, Dept Neurol, Rochester, MN USA, [3R-BRAIN] Mayo Clin, Dept Neurol, Rochester, MN USA, [Kahn, R. S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA, [Karlsson, H.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Karlsson, L.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Karlsson, H.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Karlsson, L.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Tuulari, J. J.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Karlsson, H.] Turku Univ Hosp, Turku, Finland, [Karlsson, L.] Turku Univ Hosp, Turku, Finland, [Tuulari, J. J.] Turku Univ Hosp, Turku, Finland, [Karlsson, H.] Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland, [Karlsson, L.] Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland, [Karlsson, H.] Univ Turku, Turku, Finland, [Karlsson, L.] Univ Turku, Turku, Finland, [Kawashima, R.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Taki, Y.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Thyreau, B.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Kelley, E. A.] Queens Univ, Ctr Neurosci Studies, Dept Psychol, Kingston, ON, Canada, [Kelley, E. A.] Queens Univ, Ctr Neurosci Studies, Dept Psychiat, Kingston, ON, Canada, [Kern, S.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Skoog, I.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Zettergren, A.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Kern, S.] Sahlgrens Univ Hosp, Psychiat Cognit & Old Age Psychiat Clin, Reg Vastra Gotaland, Gothenburg, Sweden, [Skoog, I.] Sahlgrens Univ Hosp, Psychiat Cognit & Old Age Psychiat Clin, Reg Vastra Gotaland, Gothenburg, Sweden, [Kim, K. W.] Seoul Natl Univ, Dept Brain & Cognit Sci, Coll Nat Sci, Seoul, South Korea, [Kim, K. W.] Seoul Natl Univ, Bundang Hosp, Dept Neuropsychiat, Seongnam, South Korea, [Kim, K. W.] Seoul Natl Univ, Dept Psychiat, Coll Med, Seoul, South Korea, [Kim, K. W.] SNU MRC, Inst Human Behav Med, Seoul, South Korea, [Lalonde, F.] NIMH, Sect Dev Neurogenom, Human Genet Branch, Bethesda, MD 20892 USA, [Raznahan, A.] NIMH, Sect Dev Neurogenom, Human Genet Branch, Bethesda, MD 20892 USA, [Lee, S.] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, Seoul, South Korea, [Lerch, J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada, [Lerch, J.] Univ Oxford, Nuffield Dept Clin Neurosci, FMRIB, Wellcome Ctr Integrat Neuroimaging, Oxford, England, [Lewis, J. D.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada, [Li, J.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Liao, W.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Valdes-Sosa, P. A.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Liston, C.] Weill Cornell Med, Dept Psychiat, New York, NY USA, [Liston, C.] Weill Cornell Med, Brain & Mind Res Inst, New York, NY USA, [Lombardo, M. V.] Ist Italiano Tecnol, Ctr Neurosci & Cognit Syst UniTn, Lab Autism & Neurodev Disorders, Rovereto, Italy, [Lv, J.] Univ Sydney, Sch Biomed Engn, Sydney, NSW, Australia, [Lv, J.] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia, [Mallard, T. T.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA, [Marcelis, M.] Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, EURON,Med Ctr, Maastricht, Netherlands, [Marcelis, M.] Inst Mental Hlth Care Eindhoven GGzE, Eindhoven, Netherlands, [Markello, R. D.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Misic, B.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Vasung, L.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Mazoyer, B.] Douglas Mental Hlth Univ Inst, Ludmer Ctr Neuroinformat & Mental Hlth, Montreal, PQ, Canada, [Meaney, M. J.] Douglas Mental Hlth Univ Inst, Ludmer Ctr Neuroinformat & Mental Hlth, Montreal, PQ, Canada, [Meaney, M. J.] Singapore Inst Clin Sci, Singapore, Singapore, [Mechelli, A.] Bordeaux Univ Hosp, Bordeaux, France, [Morgan, S. E.] Univ Cambridge, Dept Comp Sci & Technol, Cambridge, England, [Morgan, S. E.] Alan Turing Inst, London, England, [Vertes, P. E.] Alan Turing Inst, London, England, [Mothersill, D.] Natl Coll Ireland, Sch Business, Dept Psychol, Dublin, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Sch Psychol, Galway, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom, Galway, Ireland, [Mothersill, D.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland, [Nigg, J.] Oregon Hlth & Sci Univ, Dept Psychiat, Sch Med, Portland, OR 97201 USA, [Ong, M. Q. W.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Qian, X.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Ortinau, C.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA, [Ossenkoppele, R.] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC, Dept Neurol,Amsterdam Neurosci, Amsterdam, Netherlands, [Ossenkoppele, R.] Lund Univ, Clin Memory Res Unit, Lund, Sweden, [Palaniyappan, L.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada, [Palaniyappan, L.] Univ Western Ontario, Brain & Mind Inst, London, ON, Canada, [Pan, P. M.] Fed Univ Sao Poalo UNIFESP, Dept Psychiat, Sao Poalo, Brazil, [Pan, P. M.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Zugman, A.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Pantelis, C.] Univ Melbourne, Dept Psychiat, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia, [Pantelis, C.] Melbourne Hlth, Carlton, Vic, Australia, [Pantelis, C.] Univ Melbourne, Melbourne Sch Engn, Parkville, Vic, Australia, [Pantelis, C.] Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia, [Park, M. M.] Western Univ, Schulich Sch Med & Dent, Dept Psychiat, London, ON, Canada, [Rollins, C. K.] Univ Montreal, Dept Psychiat, Fac Med, Montreal, PQ, Canada, [Rollins, C. K.] Univ Montreal, CHU St Justine, Montreal, PQ, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Physiol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada, [Paz-Linares, D.] Cuban Neurosci Ctr, Havana, Cuba, [Pichet Binette, A.] McGill Univ, Fac Med, Dept Psychiat, Montreal, PQ, Canada, [Villeneuve, S.] McGill Univ, Fac Med, Dept Psychiat, Montreal, PQ, Canada, [Pichet Binette, A.] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada, [Villeneuve, S.] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada, [Qiu, J.] Southwest Univ, Sch Psychol, Chongqing, Peoples R China, [Qiu, A.] Natl Univ Singapore, N1 Inst Hlth, Dept Biomed Engn, Singapore, Singapore, [Rittman, T.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England, [Tsvetanov, K. A.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England, [Rollins, C. K.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA, [Rollins, C. K.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA, [Romero-Garcia, R.] Univ Seville, Dpto Fisiol Med & Biofis, Inst Biomed Sevilla IBiS HUVR CSIC, Seville, Spain, [Rosenberg, M. D.] Univ Chicago, Dept Psychol, 5848 S Univ Ave, Chicago, IL 60637 USA, [Rosenberg, M. D.] Univ Chicago, Inst Neurosci, Chicago, IL USA, [Rowitch, D. H.] Univ Cambridge, Dept Paediat, Cambridge, England, [Rowitch, D. H.] Univ Cambridge, Wellcome MRC Cambridge Stem Cell Inst, Cambridge, England, [Salum, G. A.] Univ Fed Rio Grande Sul UFRGS, Hosp Clin Porto Alegre, Dept Psychiat, Porto Alegre, RS, Brazil, [Salum, G. A.] Natl Inst Dev Psychiat INPD, Sao Paulo, Brazil, [Schaare, H. L.] Max Planck Inst Human Cognit & Brain Sci, Otto Hahn Grp Cognit Neurogenet, Leipzig, Germany, [Schaare, H. L.] Res Ctr Juelich, Inst Neurosci & Med INM 7 Brain & Behav, Julich, Germany, [Schultz, A. P.] Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA, [Schumann, G.] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Ctr Populat Neurosci & Stratified Med PONS, Shanghai, Peoples R China, [Schumann, G.] Charite Campus Mitte, Dept Psychiat & Psychotherapy, Charite Mental Hlth, PONS Ctr, Berlin, Germany, [Scholl, M.] Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden, [Scholl, M.] Univ Gothenburg, Dept Psychiat & Neurochem, Gothenburg, Sweden, [Scholl, M.] UCL, Queens Sq Inst Neurol, Dementia Res Ctr, London, England, [Sharp, D.] UK Dementia Res Inst, Care Res & Technol Ctr, London, England, [Shinohara, R. T.] Univ Penn, Perelman Sch Med, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA, [Stein, D. J.] Univ Cape Town, Dept Psychiat, SA MRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa, [Stein, D. J.] Univ Cape Town, Neurosci Inst, Cape Town, South Africa, [Stolicyn, A.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Whalley, H. C.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Toro, R.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Univ Paris 05, Ctr Res & Interdisciplinar CRI, Paris, France, [Tsvetanov, K. A.] Univ Cambridge, Dept Psychol, Cambridge, England, [Turk-Browne, N. B.] Yale Univ, Wu Tsai Inst, New Haven, CT USA, [Tuulari, J. J.] Univ Turku, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Turku Coll Sci Med & Technol, Turku, Finland, [Tzourio, C.] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, CHU Bordeaux, U1219,INSERM, Bordeaux, France, [Vachon-Presseau, E.] McGill Univ, Fac Dent Med & Oral Hlth Sci, Montreal, PQ, Canada, [Valdes-Sosa, P. A.] McGill Univ, Alan Edwards Ctr Res Pain AECRP, Montreal, PQ, Canada, [Valk, S. L.] Forschungszentrum Julich, Inst Neurosci & Med 7, Julich, Germany, [Valk, S. L.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany, [van Amelsvoort, T.] Maastricht Univ, Dept Psychiat & Neurosychol, Maastricht, Netherlands, [Vandekar, S. N.] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA, [Villeneuve, S.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA, [Villringer, A.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Witte, A. V.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Zuo, X. N.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Wang, Y. S.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yeo, B.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Wang, Y. S.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Wang, Y. S.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Yang, N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Zuo, X. N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Wang, Y. S.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Yang, N.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Westman, E.] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden, [Witte, A. V.] Univ Leipzig, CRC 1052 Obes Mech, Fac Med, Leipzig, Germany, [Zhou, J. H.] Natl Univ Singapore, Dept Elect & Comp Engn, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat MR Res, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, N1 Inst Hlth, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Inst Digital Med, Singapore, Singapore, [Yun, H.] Natl Univ Singapore, Integrat Sci & Engn Programme ISEP, Singapore, Singapore, [Zar, H. J.] Univ Melbourne, Dept Biomed Engn, Melbourne, Vic, Australia, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat Magnet Resonance Res, Singapore, Singapore, [Ziauddeen, H.] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Cambridge, England, [Zugman, A.] NIMH, NIH, Bethesda, MD 20892 USA, [Zugman, A.] Escola Paulista Med, Dept Psychiat, Sao Paulo, Brazil, [Zuo, X. N.] Nanning Normal Univ, Sch Educ Sci, Key Lab Brain & Educ, Nanning, Peoples R China, British Academy Postdoctoral fellowship, NIMH, UKRI Medical Research Council, NIHR Cambridge Biomedical Research Centre, NIHR Senior Investigator award, MRC research infrastructure award, Commonwealth Scientific and Industrial Research Organisation (CSIRO), and Ontario Brain Institute
Subjects: 631/378/2649, OpenPain Project, KNE96, Growth, Psychiatric-disorders, DISEASE, 3R-BRAIN, Brain charts, MRI Brain, OASIS-3, Disease, CCNP, 631/378/2571, UMN BCP, Multidisciplinary, medicine.diagnostic_test, PSYCHIATRIC-DISORDERS, article, Brain, Human brain, ASSOCIATION, Magnetic Resonance Imaging, Harvard Aging Brain Study, The Mayo Clinic Study of Aging, NSPN, medicine.anatomical_structure, GROWTH, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:500, BURDEN, WHITE-MATTER, FinnBrain, Harvard Aging Brain Study, Organization, Mri, MRI, medicine.medical_specialty, Concurrent validity, MODELS, Cam-CAN, Longevity, CALM Team, POND, Neuroimaging, Burden, ORGANIZATION, AIBL, The PREVENT-AD Research Group, VETSA, Cortical thickness, Association, Physical medicine and rehabilitation, FinnBrain, IMAGEN, KNE96, White-matter, medicine, Humans, ASRB, 631/378/1689, COBRE, business.industry, 631/378/2611, Brain morphometry, Neurosciences, Alzheimer’s Disease Repository Without Borders Investigators, Magnetic resonance imaging, Alzheimer’s Disease Neuroimaging Initiative, Anthropometry, Body Height, Brain growth, Birth, 59/57, Normative, IMAGEN, ENIGMA Developmental Brain Age working group, NSPN, business, CCNP, 3R-BRAIN, CORTICAL THICKNESS, Developing Human Connectome Project, ENIGMA Developmental Brain Age working group, The PREVENT-AD Research Group, VETSA, Bullmore, E.T
Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.
Published: 2022

26. Deep learning-based system for real-time behavior recognition and closed-loop control of behavioral mazes using depth sensing

Author: Ana Gerós, Ricardo Cruz, Fabrice de Chaumont, Jaime S. Cardoso, Paulo Aguiar, Universidade do Porto = University of Porto, 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), and This work was partially financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the projects PTDC/EMD-EMD/31540/2017 (POCI-01-0145- FEDER-031540). We acknowledge the support of the i3S Animal House facility. Ana Gerós was funded by FCT – Fundação para a Ciência e a Tecnologia, grant contract SFRH/BD/137385/2018.
Subjects: [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], [SDV]Life Sciences [q-bio], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: Robust quantification of animal behavior is fundamental in experimental neuroscience research. Systems providing automated behavioral assessment are an important alternative to manual measurements avoiding problems such as human bias, low reproducibility and high cost. Integrating these tools with closed-loop control systems creates conditions to correlate environment and behavioral expressions effectively, and ultimately explain the neural foundations of behavior. We present an integrated solution for automated behavioral analysis of rodents using deep learning networks on video streams acquired from a depth-sensing camera. The use of depth sensors has notable advantages: tracking/classification performance is improved and independent of animals’ coat color, and videos can be recorded in dark conditions without affecting animals’ natural behavior. Convolutional and recurrent layers were combined in deep network architectures, and both spatial and temporal representations were successfully learned for a 4- classes behavior classification task (standstill, walking, rearing and grooming). Integration with Arduino microcontrollers creates an easy-to-use control platform providing low-latency feedback signals based on the deep learning automatic classification of animal behavior. The complete system, combining depth-sensor camera, computer, and Arduino microcontroller, allows simple mapping of input-output control signals using the animal’s current behavior and position. For example, a feeder can be controlled not by pressing a lever but by the animal behavior itself. An integrated graphical user interface completes a user-friendly and cost-effective solution for animal tracking and behavior classification. This open-software/open-hardware platform can boost the development of customized protocols for automated behavioral research, and support ever more sophisticated, reliable and reproducible behavioral neuroscience experiments.
Published: 2022

27. The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions

Author: Jennifer Cooke, Ciara J. Molloy, Antonia San José Cáceres, Thomas Dinneen, Thomas Bourgeron, Declan Murphy, Louise Gallagher, Eva Loth, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Trinity College Dublin, Hospital General Universitario 'Gregorio Marañón' [Madrid], Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), 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), This work was supported by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. This work was also supported by the Science Foundation Ireland grant 13/IA/1787., and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: synaptopathies, General Neuroscience, NRXN1 deletion, autism, biomarker, Phelan-McDermid syndrome, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurosciences. Biological psychiatry. Neuropsychiatry, rare genetic variants, RC321-571
Abstract: Synaptic gene conditions, i.e., “synaptopathies,” involve disruption to genes expressed at the synapse and account for between 0.5 and 2% of autism cases. They provide a unique entry point to understanding the molecular and biological mechanisms underpinning autism-related phenotypes. Phelan-McDermid Syndrome (PMS, also known as 22q13 deletion syndrome) and NRXN1 deletions (NRXN1ds) are two synaptopathies associated with autism and related neurodevelopmental disorders (NDDs). PMS often incorporates disruption to the SHANK3 gene, implicated in excitatory postsynaptic scaffolding, whereas the NRXN1 gene encodes neurexin-1, a presynaptic cell adhesion protein; both are implicated in trans-synaptic signaling in the brain. Around 70% of individuals with PMS and 43–70% of those with NRXN1ds receive a diagnosis of autism, suggesting that alterations in synaptic development may play a crucial role in explaining the aetiology of autism. However, a substantial amount of heterogeneity exists between conditions. Most individuals with PMS have moderate to profound intellectual disability (ID), while those with NRXN1ds have no ID to severe ID. Speech abnormalities are common to both, although appear more severe in PMS. Very little is currently known about the neurocognitive underpinnings of phenotypic presentations in PMS and NRXN1ds. The Synaptic Gene (SynaG) study adopts a gene-first approach and comprehensively assesses these two syndromic forms of autism. The study compliments preclinical efforts within AIMS-2-TRIALS focused on SHANK3 and NRXN1. The aims of the study are to (1) establish the frequency of autism diagnosis and features in individuals with PMS and NRXN1ds, (2) to compare the clinical profile of PMS, NRXN1ds, and individuals with ‘idiopathic’ autism (iASD), (3) to identify mechanistic biomarkers that may account for autistic features and/or heterogeneity in clinical profiles, and (4) investigate the impact of second or multiple genetic hits on heterogeneity in clinical profiles. In the current paper we describe our methodology for phenotyping the sample and our planned comparisons, with information on the necessary adaptations made during the global COVID-19 pandemic. We also describe the demographics of the data collected thus far, including 25 PMS, 36 NRXN1ds, 33 iASD, and 52 NTD participants, and present an interim analysis of autistic features and adaptive functioning.
Published: 2022

28. Stratifying the autistic phenotype using electrophysiological indices of social perception

Author: Luke Mason, Carolin Moessnang, Christopher Chatham, Lindsay Ham, Julian Tillmann, Guillaume Dumas, Claire Ellis, Claire S. Leblond, Freddy Cliquet, Thomas Bourgeron, Christian Beckmann, Tony Charman, Beth Oakley, Tobias Banaschewski, Andreas Meyer-Lindenberg, Simon Baron-Cohen, Sven Bölte, Jan K. Buitelaar, Sarah Durston, Eva Loth, Bob Oranje, Antonio Persico, Flavio Dell’Acqua, Christine Ecker, Mark H. Johnson, Declan Murphy, Emily J. H. Jones, University of London [London], Universität Heidelberg [Heidelberg] = Heidelberg University, F. Hoffmann-La Roche [Basel], King‘s College London, 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], Radboud University Medical Center [Nijmegen], Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Heidelberg University, University of Cambridge [UK] (CAM), Stockholm Health Care Services (SLSO), University Medical Center [Utrecht], Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), Curtin University [Perth], Planning and Transport Research Centre (PATREC), Roche Pharma Research and Early Development [Basel] (pRED), This project has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution (E.J.H.J., M.J., T.C., and D.M.), and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 (E.J.H.J., M.J., T.C., and D.M.). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and AUTISM SPEAKS, Autistica, SFARI, awards from the Medical Research Council (MR/K021389/1, MR/T003057/1, E.J.H.J., M.J., and T.C.)., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: Evoked Potentials, Humans, Phenotype, Social Perception, Autism Spectrum Disorder, Autistic Disorder, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, fMRI, 220 Statistical Imaging Neuroscience, autism, General Medicine, 130 000 Cognitive Neurology & Memory, polygenic score, N170 latence
Abstract: Contains fulltext : 282637.pdf (Publisher’s version ) (Closed access) Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD.
Published: 2022

29. Early Systemic Inflammation Induces Neurodevelopmental Disorders: Results from Artemis, a French Multicenter Study of Juvenile Rheumatisms and Systemic Autoimmune and Auto-Inflammatory Disorders and Meta-Analysis

Author: Pierre Ellul, Isabelle Melki, Stephanie Antoun, Laura Lavialle, Eric Acquaviva, Florence A. Aeschlimann, Brigitte Bader-Meunier, Alexandre Belot, Glory Dingulu, Cecile Dumaine, Albert Faye, Marie-Louise Frémond, Ulrich Meinzer, Hugo Peyre, Pierre Quartier, Michelle Rosenzwajg, Isabelle Savioz, Caroline Vinit, Nicolas Tchitchek, David Klatzmann, Richard Delorme, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques [CHU Necker] (RAISE), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie, rhumatologie et dermatologie pédiatriques [Hôpital Femme Mère Enfant, HCL], Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, Hôpital Robert Debré Paris, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), and The authors received funding from DM’UP (Robert Debré).
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, History, Polymers and Plastics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Business and International Management, Molecular Biology, Industrial and Manufacturing Engineering
Abstract: International audience
Published: 2022

30. Machine learning for neurodevelopmental disorders

Author: Moreau, Clara, Deruelle, Christine, Auzias, Guillaume, 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), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), ANR-19-CE45-0014,SulcalGRIDS,Dynamique de la morphologie corticale chez l'enfant(2019), Auzias, guillaume, and Dynamique de la morphologie corticale chez l'enfant - - SulcalGRIDS2019 - ANR-19-CE45-0014 - AAPG2019 - VALID
Subjects: Autism Spectrum Disorders, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Pattern recognition, Neurodevelopmental disorders, Machine learning, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Stratification, Classification, Attention Deficit Hyperactivity Disorders, Clustering
Abstract: International audience; Neurodevelopmental disorders (NDDs) constitute a major health issue with >10% of the general worldwide population affected by at least one of these conditions-such as Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorders (ADHD). Each NDD is particularly complex to dissect for several reasons, including a high prevalence of comorbidities and a substantial heterogeneity of the clinical presentation. At the genetic level, several thousands of genes have been identified (polygenicity), while a part of them was already involved in other psychiatric conditions (pleiotropy). Given these multiple sources of variance, gathering sufficient data for the proper application and evaluation of machine learning (ML) techniques is essential but challenging. In this chapter, we offer an overview of the ML methods most widely used to tackle NDDs complexity-from stratification techniques to diagnosis prediction. We point out challenges specific to NDDs such as early diagnosis, that can benefit from the recent advances in the ML field. These techniques also have the potential to delineate homogeneous subgroups of patients that would enable a refined understanding of underlying physiopathology. We finally survey a selection of recent papers that we consider as particularly representative of the opportunities offered by contemporary ML techniques applied to large open datasets, or that illustrate the challenges faced by current approaches to be addressed in the near future.
Published: 2022

31. Phelan-McDermid syndrome: a classification system after 30 years of experience

Author: Katy Phelan, Luigi Boccuto, Craig M. Powell, Tobias M. Boeckers, Conny van Ravenswaaij-Arts, R. Curtis Rogers, Carlo Sala, Chiara Verpelli, Audrey Thurm, William E. Bennett, Christopher J. Winrow, Sheldon R. Garrison, Roberto Toro, Thomas Bourgeron, Florida Cancer Specialists [Fort Myers, FL], Clemson University, University of Alabama at Birmingham [ Birmingham] (UAB), Universität Ulm - Ulm University [Ulm, Allemagne], University of Groningen [Groningen], The Greenwood Genetic Center, Istituto di Neuroscienze - Institute of Neuroscience [Milan, Italy] (CNR), Università degli Studi di Milano = University of Milan (UNIMI)-Consiglio Nazionale delle Ricerche [Milano] (CNR), National Institute of Mental Health (NIMH), National Institutes of Health [Bethesda] (NIH), Indiana University School of Medicine, Indiana University System, Cyclerion Therapeutics [Cambridge, MA], Rogers Behavioral Health [Oconomowoc, WI], 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), No funding sources were utilized in the preparation of this article, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Chromosomes, Human, Pair 22, Phelan-McDermid syndrome PMS SHANK3 22q13 deletion, PMS, Chromosome Disorders, General Medicine, 22q13 deletion, Phenotype, Medicine, Phelan-McDermid syndrome, Humans, Pharmacology (medical), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chromosome Deletion, Letter to the Editor, SHANK3, Genetics (clinical)
Abstract: Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to “lose” their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.
Published: 2022

32. Dark control: The default mode network as a reinforcement learning agent

Author: Danilo Bzdok, Guillaume Dumas, Elvis Dohmatob, Modelling brain structure, function and variability based on high-field MRI data (PARIETAL), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Criteo AI Lab, Criteo [Paris], IFR49 - Neurospin - CEA, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Montreal Institute for Learning Algorithms [Montréal] (MILA), Centre de Recherches Mathématiques [Montréal] (CRM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Montreal Neurological Hospital, McGill University Health Center [Montreal] (MUHC), McGill University = Université McGill [Montréal, Canada], Innovative Medicines Initiative, Grant/Award Number: 777394, Seventh Framework Programme, Grant/Award Number: 604102, Studienstiftung des Deutschen Volkes, Canada Institute for Advanced Research, Canada First Research Excellence fund, Exploratory Research Space, Grant/Award Number: OPSF449, START‐Program of the Faculty of Medicine, Grant/Award Number: 126/16, German National Merit Foundation, Amazon AWS Research Grant, International Research Training Group, Grant/Award Number: IRTG2150, Deutsche Forschungsgemeinschaft, Grant/Award Numbers: BZ2/4‐1, BZ2/3‐1, BZ2/2‐1, European Project: 604102,EC:FP7:ICT,FP7-ICT-2013-FET-F,HBP(2013), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Computer science, media_common.quotation_subject, human intelligence, systems neuroscience, Hippocampus, 050105 experimental psychology, Thinking, 03 medical and health sciences, [SCCO]Cognitive science, Executive Function, 0302 clinical medicine, Mind-wandering, Reinforcement learning, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Function (engineering), Default mode network, Research Articles, media_common, Cerebral Cortex, Radiological and Ultrasound Technology, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, Perspective (graphical), Default Mode Network, mind-wandering, Models, Theoretical, Trial and error, artificial intelligence, Anticipation, Psychological, Markov Chains, Neurology, Action (philosophy), Neurology (clinical), Markov decision process, Anatomy, Reinforcement, Psychology, 030217 neurology & neurosurgery, Cognitive psychology, Research Article
Abstract: International audience; The default mode network (DMN) is believed to subserve the baseline mental activity in humans. Its higher energy consumption compared to other brain networks and its intimate coupling with conscious awareness are both pointing to an unknown overarching function. Many research streams speak in favor of an evolutionarily adaptive role in envisioning experience to anticipate the future. In the present work, we propose a process model that tries to explain how the DMN may implement continuous evaluation and prediction of the environment to guide behavior. The main purpose of DMN activity, we argue, may be described by Markov Decision Processes that optimize action policies via value estimates based through vicarious trial and error. Our formal perspective on DMN function naturally accommodates as special cases previous interpretations based on (1) predictive coding, (2) semantic associations, and (3) a sentinel role. Moreover, this process model for the neural optimization of complex behavior in the DMN offers parsimonious explanations for recent experimental findings in animals and humans.
Published: 2020

33. Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author: Ashley N. Sigafoos, Salima El Chehadeh, Marcia C. Willing, Ela Akay, Florian Cherik, Anne-Marie E. Goyette, Vinodh Narayanan, Diane Masser-Frye, Catherine Karimov, Rhonda E. Schnur, Rebekah Bressi, Rhys H. Thomas, Gary D. Clark, Tina Barbaro-Dieber, Jill A. Rosenfeld, Carlos A. Bacino, Maria J. Guillen Sacoto, Laura Russell, Kristin Lindstrom, Caroline Schluth-Bolard, Xia Wang, Yvonne Hilhorst-Hofstee, Marcelo Vargas, Zehua Zhu, Ash Zawerton, Boris Keren, Mariëtte J.V. Hoffer, Isabelle Marey, Alice Poisson, Daphné Lehalle, Maries Joseph, Gaetan Lesca, Simon Zwolinski, Laurence Perrin, Rhoda Akilapa, Emilia K. Bijlsma, Christel Depienne, Amélie Piton, Claire G. Salter, Lucie Dupuis, Daryl A. Scott, Jolien S. Klein Wassink-Ruiter, Benjamin Cogné, Mathilde Nizon, Richard Chang, Kirsty McWalter, Myriam Srour, Perrine Charles, Anne-Claude Tabet, Natalie Canham, Sylvie Odent, Caroline Nava, Karl J. Clark, Elizabeth J. Bhoj, Jonathan Levy, Keri Ramsey, Yves Alembik, Lucia Ortega, Sophie Dupuis-Girod, Shoji Ichikawa, Christine Francannet, Marta Bertoli, Christèle Dubourg, Eric W. Klee, Ange-Line Bruel, Sebastien Moutton, Emily Fassi, Anthony Vandersteen, Abdul Haseeb, Antonina Wojcik, Patrick R. Blackburn, Lynne M. Bird, Patrick Rump, Véronique Lefebvre, Alma Kuechler, Sophie Nambot, Keren Machol, Cyril Mignot, Andreas Hartmann, Rossana Sanchez Russo, Erica H. Gerkes, Sylvie Jaillard, Roberto Mendoza-Londono, Trevor Cole, Pauline Monin, Cleveland Clinic, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, This research was funded in part by the Agence Nationale de la Recherche and European High-Functioning Autism Network (ANR EUHFAUTISM), the Assistance Publique–Hôpitaux de Paris (AP-HP), the Institut National de la Santé et de la Recherche Médicale (INSERM), the BioPsy labex (to Christel Depienne and C.N.) and the Association Française du Syndrome Gilles de la Tourette (AFSGT) to Christel Depienne. It was also funded by the Cleveland Clinic Lerner Research Institute (LRI Chair’s Innovative Research Award to V.L.), and by Harper’s Quest and the LAMSHF Syndrome Research Fund (donations to V.L.) and the Center for Individualized Medicine, Mayo Clinic. This study makes use of data generated by the DECIPHER community and the Deciphering Developmental Disorders (DDD) Study, which is funded by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network., We thank the patients and their families for their participation in this study, and the C4RCD Research Group (Newell Belnap, Amanda Courtright, Ana Claasen, David Craig, Matt Huentelman, Madison LaFleur, Sampathkumar Rangasamy, Ryan Richholt, Isabelle Schrauwen, Ashley L. Siniard, and Szabolics Szelinger) for providing clinical information on patient P18., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre d'Exploration et de Recherche Médicales par Émission de Positons (CERMEP), Université Joseph Fourier - Grenoble 1 (UJF)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Medizin, Haploinsufficiency, L-SOX5, VARIANTS, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Genetics, Pediatric, Genetics & Heredity, 0303 health sciences, Pedigree, FAMILY, DNA-Binding Proteins, developmental delay, TRANSCRIPTION FACTORS, Phenotype, intellectual disability, Child, Preschool, missense variants, Female, SOXD Transcription Factors, Adult, EXPRESSION, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Mutation, Missense, autism, Cell fate determination, Biology, LONG FORM, SEQUENCE, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, CARTILAGE, Intellectual Disability, medicine, Animals, Humans, Language Development Disorders, Genetic Predisposition to Disease, Preschool, Transcription factor, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, Human Genome, Infant, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, Deciphering Developmental Disorder Study, Mutation, Autism, epilepsy, Missense, 030217 neurology & neurosurgery, GENERATION
Abstract: International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Published: 2020

34. Do not Dispose of Historic Fluid Collections: Evaluating Research Potential and Range of Use

Author: M. Herbin, M.D. Santin, R. Toro, K. Heuer, J. Cuisin, C. Martin, L. Raveendran, C. François, R. Debruyne, Mécanismes Adaptatifs et Evolution (MECADEV), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Direction générale déléguée à la Recherche, à l’Expertise, à la Valorisation et à l’Enseignement-Formation (DGD.REVE), and This work was supported by ATM-MNHN Blanche 2019 'COLL-FLUID-ADN,' and by grant from Direction des collections, MNHN for 'Brain Catalogue project.'
Subjects: Owen’s liquor, Fluid-preservation, Ethanol, [SDV]Life Sciences [q-bio], Rehabilitation, Macroscopic, Comparative analysis, Molecular, Physical Therapy, Sports Therapy and Rehabilitation, General Medicine, Mammalian brain, Historic collections, Microscopic, Formaldehyde
Abstract: International audience; The use of specific preservative solutions by museum professionals to maintain fluid-preserved specimens has fluctuated over the years with advances in chemistry. The determining factors for the original choice of solution closely correlate with the historical parameters and original usage of the collections. Consequently, for any given collection, changes and substitutions over time in the types of preservative fluids used have likely occurred. The present comparative analysis of the state of brain preservation, carried out at macroscopic, microscopic, and molecular levels, allowed us to evaluate the effect of the different treatments applied over time to fluid-preserved collections. Our results confirm that the duration of formaldehyde exposure of the tissues clearly has an effect on their long-term preservation. Despite the controversies associated with the quality or use of some historic fixatives, modern analytical methods such as medical imagery reveal the preservation quality in historic specimens and their potential for future research use. However, the choice of fixatives and storage fluids to preserve the specimens is of critical importance because today's choices will influence the use of the specimen for advanced analytical methods in the future.; Au cours des époques, les solutions de conservation utilisées dans les collections en fluides ont changé avec les progrès de la chimie. Le choix initial de la solution de conservation est souvent étroitement lié à, l’époque, et à l’utilisation originale des échantillons. Par conséquent, dans une collection donnée, plusieurs changements de solution de conservation ont pu avoir lieu au courant du temps. L’analyse macroscopique, microscopique et moléculaire de l’état de conservation des cerveaux, nous a permis d’évaluer les effets des différents traitements appliqués au cours du temps à ces collections en fluide. Nos résultats confirment que la durée d’exposition au formaldéhyde a clairement un effet sur les tissus préservés. Malgré les controverses associées à la qualité ou l’utilisation de certains fixateurs historiques, les méthodes analytiques modernes telles que l’imagerie médicale prouvent la qualité de conservation des spécimens historiques et leur potentiel pour leur utilisation future en recherche. Cependant, le choix du fluide de fixation et de conservation est d’une importance cruciale car les choix d’aujourd’hui influenceront l’utilisation des spécimens à l’aide des nouvelles méthodes d’analyse de demain.
Published: 2020

35. Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series

Author: Marion Lesieur‐Sebellin, Marianne Till, Philippe Khau Van Kien, Bérénice Herve, Nicolas Bourgon, Céline Dupont, Anne‐Claude Tabet, Mathilde Barrois, Aurélie Coussement, Laurence Loeuillet, Eve Mousty, Vuthy Ea, Amal Assal, Laura Mary, Sylvie Jaillard, Claire Beneteau, Claudine Le Vaillant, Charles Coutton, Françoise Devillard, Carole Goumy, Amélie Delabaere, Sylvia Redon, Yves Laurent, Audrey Lamouroux, Jérôme Massardier, Catherine Turleau, Damien Sanlaville, Vincent Cantagrel, Pascale Sonigo, François Vialard, Laurent J. Salomon, Valérie Malan, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), AP-HP Hôpital universitaire Robert-Debré [Paris], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Maternité Port-Royal [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHI Poissy-Saint-Germain, CHU Pontchaillou [Rennes], École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes (CHU Nantes), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe Hospitalier Bretagne Sud (GHBS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Brest (UBO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Cité (UPCité), Service Obstétrique [CHU Clermont-Ferrand], Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Thérapie guidée par l'image (TGI), and SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)-SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, phenotype mimicking heterozygous, INTELLECTUAL DISABILITY, [SDV]Life Sciences [q-bio], Chromosome Disorders, Trisomy, LONG ARM, brain malformations, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, Pregnancy, FETUSES, MICROARRAY ANALYSIS, Humans, pathogenic variants, Genetics (clinical), 030304 developmental biology, Retrospective Studies, 0303 health sciences, Virulence, DEVELOPMENTAL DELAY, ABNORMALITIES, 030305 genetics & heredity, Calcium-Binding Proteins, REARRANGEMENTS, Obstetrics and Gynecology, Membrane Proteins, deletions, 3. Good health, NOTCH, Phenotype, DIFFERENTIATION, Chromosomes, Human, Pair 6, Female, MENTAL-RETARDATION
Abstract: International audience; OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.
Published: 2021

36. The meaning of significant mean group differences for biomarker discovery

Author: Jennifer Cooke, Danilo Bzdok, Declan G. Murphy, Bethany Oakley, Hannah Hayward, Emily J.H. Jones, Roberto Toro, Antonia San José Cáceres, Guillaume Dumas, Thomas Bourgeron, Tony Charman, Christopher H. Chatham, Christian F. Beckmann, Beatriz López, Jan K. Buitelaar, Daisy Crawley, Ben Carter, Jumana Ahmad, Eva Loth, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Greenwich, F. Hoffmann-La Roche [Basel], University of Portsmouth, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Centre for Brain and Cognitive Development [Birkbeck College], Birkbeck College [University of London], Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], 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), CHU Sainte Justine [Montréal], Quebec Artificial Intelligence Institute (Mila), EL, JA, BL, BC, DC, BO, HH, JC, ASJC, EJ, TC, CB, TB, RT, JB, DM, and GD have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking is a joint support from the European Union's Horizon 2020 research and innovation programme, EFPIA, AUTISM SPEAKS, Autistica, and SFARI., and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: Pervasive Developmental Disorders, Autism Spectrum Disorder, Autism, Individuality, Normal Distribution, Theory of Mind, Social Sciences, Biochemistry, Standard deviation, Medical Conditions, Mathematical and Statistical Techniques, Theory of mind, Statistics, Medicine and Health Sciences, Psychology, Biology (General), Biomarker discovery, Ecology, Mental Disorders, Metaanalysis, Neuropsychiatry, Computational Theory and Mathematics, Neurology, Modeling and Simulation, Physical Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Statistical Distributions, QH301-705.5, Research and Analysis Methods, Skewness, Education, Normal distribution, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuropsychology, Genetics, medicine, Humans, Computer Simulation, Meaning (existential), Autistic Disorder, Statistical Methods, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Cognitive Psychology, Computational Biology, Biology and Life Sciences, medicine.disease, Probability Theory, Probability Distribution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Sample size determination, Neurodevelopmental Disorders, Case-Control Studies, Sample Size, Developmental Psychology, Cognitive Science, Biomarkers, Mathematics, Neuroscience
Abstract: Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between “cases” and “controls,” which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research—autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen’s d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the “on average” when summarising their findings in their abstracts (“autistic people have deficits in X”), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers., Author summary Currently, a striking paradox is often found in neuropsychiatric research. On the one hand, most clinicians and researchers accept that many neuropsychiatric conditions involve tremendous individual variability. On the other hand, the prevailing statistical approach is still the mean group comparison between “cases” and “controls.” Statistically significant mean group differences tell us that a given characteristic in brain, behaviour, or genes is on average different between the 2 groups. Yet, they do not delineate variability within groups. Moreover, using autism research as an example, we show that in up to 95% of abstracts, when reporting or interpreting findings, researchers omit the “on average.” This can be misleading because it evokes the impression as though the group-level difference would generalise to all individuals with that condition. Here, we used simulations to show that the latter statement is only true at very large effect sizes. We demonstrate that across different areas of autism research, mean group differences with small to large effects indicate that approximately 45% to 68% [cases] do not have an atypicality on cognitive tests or brain structure. However, we also show that across normal and nonnormal distributions, subgroups may exist despite small or nonsignificant overall effects. We propose practical approaches and steps for researchers to use mean group comparisons as the starting point for the discovery of clinically relevant subgroups.
Published: 2021

37. Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons

Author: Eric Senabre Marchan, Rafael Maldonado, Marie-Charlotte Allichon, Andry Andrianarivelo, Jocelyne Caboche, Jean-Antoine Girault, Arthur Godino, Peter Vanhoutte, Benoit Forget, Vincent Kappes, Laura Domingo Rodriguez, Mélanie Marias, Elena Martin Garcia, Pierre Poirier, Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Universitat Pompeu Fabra [Barcelona] (UPF), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Saints-Pères Paris Institute for Neurosciences (SPPIN - UMR 8003), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physiologie cérébrale (LPC - UMR 8118), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), This work was supported by Fondation pour la Recherche Médicale (DEQ20150734352 to JC), Centre National pour la Recherche Scientifique (CNRS, B.F., A.G., V.K., P.P., P.V., J.C.), Institut National pour la Santé et la Recherche Médicale (INSERM, B.F., A.G., V.K., P.P., P.V., J.-A.G., J.C.), Sorbonne Université, Faculté des Sciences et Ingénierie (B.F., A.G., V.K., P.P., P.V., J.-A.G., J.C.) Labex Biopsy Investissements d’Avenir, ANR-11-IDEX-0004-02 (B.F., A.G., V.K., P.P., P.V., J.-A.G., J.C.), the Spanish Ministerio de Economía y Competitividad-MINECO (#SAF2017-84060-R-AEI/FEDER-UE, E.M.-G., L.D.-R., R.M.), the Spanish Instituto de Salud Carlos III, RETICS-RTA (#RD12/0028/0023, E.M.-G., L.D.-R., R.M.), the Generalitat de Catalunya, AGAUR (#2017-SGR-669, E.M.-G., L.D.-R., R.M.), ICREA-Acadèmia (#2015) and the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas (#PNSD-2017I068) to R.M., Fundació La Marató-TV3 (#2016/20-30) to E.M.-G. Fondation pour la Recherche Médicale (FRM#DPA20140629798) and ANR (ANR-16-CE16-0018) to J.A.G., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-16-CE16-0018,EPITRACES,Traces épigénétiques neuronales des récompenses(2016), B.F., A.G., V.K., P.P., P.V., J.-A.G, J.C), Sorbonne Université, Faculté des Sciences et Ingénierie (B.F., A.G., V.K., P.P., P.V., J.-A.G, J.C) Labex Biopsy Investissements d’Avenir, ANR-11-IDEX-0004-02 (B.F., A.G., V.K., P.P., P.V., J.-A.G, J.C), the Spanish Ministerio de Economía y Competitividad-MINECO (#SAF2017-84060-R-AEI/FEDER-UE, E.M.-G., L.D.-R., R.M.), ICREA-Acadèmia (#2015) and the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas (#PNSD-2017I068) to R.M., Fundació La Marató-TV3 (#2016/20-30) to E.M.-G, Fondation pour la Recherche Médicale (FRM#DPA20140629798) and ANR (ANR-16-CE16-0018) to J.A.G., caboche, jocelyne, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Traces épigénétiques neuronales des récompenses - - EPITRACES2016 - ANR-16-CE16-0018 - AAPG2016 - VALID, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Cell type, Molecular biology, Physiology, [SDV]Life Sciences [q-bio], Cell, Self Administration, Striatum, Nucleus accumbens, Biology, Nucleus Accumbens, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Downregulation and upregulation, Cocaine, microRNA, medicine, Basic Helix-Loop-Helix Transcription Factors, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030304 developmental biology, Neurons, 0303 health sciences, Receptors, Dopamine D1, Psychiatry and Mental health, MicroRNAs, medicine.anatomical_structure, Dopamine receptor, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, FOSB
Abstract: The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations. This work was supported by Fondation pour la Recherche Médicale (DEQ20150734352 to JC), Centre National pour la Recherche Scientifique (CNRS, B.F., A.G., V.K., P.P., P.V., J.C.), Institut National pour la Santé et la Recherche Médicale (INSERM; B.F., A.G., V.K., P.P., P.V., J.-A.G., J.C.), Sorbonne Université, Faculté des Sciences et Ingénierie (B.F., A.G., V.K., P.P., P.V., J.-A.G., J.C.) Labex Biopsy Investissements d’Avenir, ANR-11-IDEX-0004-02 (B.F., A.G., V.K., P.P., P.V., J.-A.G., J.C.), the Spanish Ministerio de Economía y Competitividad-MINECO (#SAF2017-84060-R-AEI/FEDER-UE; E.M.-G., L.D.-R., R.M.), the Spanish Instituto de Salud Carlos III, RETICS-RTA (#RD12/0028/0023; E.M.-G., L.D.-R., R.M.), the Generalitat de Catalunya, AGAUR (#2017-SGR-669; E.M.-G., L.D.-R., R.M.), ICREA-Acadèmia (#2015) and the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas (#PNSD-2017I068) to R.M., Fundació La Marató-TV3 (#2016/20-30) to E.M.-G. Fondation pour la Recherche Médicale (FRM#DPA20140629798) and ANR (ANR-16-CE16-0018) to J.A.G.
Published: 2021

38. A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

Author: Mustafa Sahin, Jacob A. S. Vorstman, Delnaz Roshandel, Alana Iaboni, Iva Pritišanac, Richard Delorme, Stephen W. Scherer, Marjolaine Willems, Mehdi Zarrei, Lynette Lau, Jennifer L. Howe, Alan M. Moses, Evdokia Anagnostou, Brianna Godlewski, Livia O Loureiro, Miriam S. Reuter, Julie D. Forman-Kay, Anne-Claude Tabet, Siddharth Srivastava, Brett Trost, Suzanne M E Lewis, Christian R. Marshall, Olivia Rennie, Thomas W. Frazier, Peter Szatmari, Thomas Bourgeron, Elizabeth D. Buttermore, Kristina Calli, Stelios Georgiades, Amélie Piton, Dean Hartley, Clarrisa A Lisa Bradley, James Lespinasse, Serge Lumbroso, The Hospital for sick children [Toronto] (SickKids), Holland Bloorview Kids Rehabilitation Hospital [Toronto, ON, Canada], University of British Columbia (UBC), University of Toronto, Department of Biochemistry [University of Toronto], Harvard Medical School [Boston] (HMS), John Carroll University, McMaster University [Hamilton, Ontario], Centre for Addiction and Mental Health [Toronto] (CAMH), 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), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Métropole Savoie [Chambéry], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Strasbourg, This work was funded by Autism Speaks, Autism Speaks Canada, the University of Toronto McLaughlin Centre, the Canada Foundation for Innovation, the Canadian Institutes of Health Research (CIHR), Genome Canada/Ontario Genomics Institute, the Government of Ontario, Brain Canada, Ontario Brain Institute Province of Ontario Neurodevelopmental Disorders (POND), and The Hospital for Sick Children Foundation. L.O.L holds Lap-Chee Tsui Postdoctoral Fellowship from The Hospital for Sick Children. S.W.S holds the Northbridge Chair in Paediatric Research at the Hospital for Sick Children and University of Toronto., and Retiveau, Nolwenn
Subjects: Proband, Genetic counseling, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, QH426-470, Biology, behavioral disciplines and activities, Article, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, mental disorders, Gene duplication, Genetics, medicine, Copy-number variation, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, medicine.disease, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, Medicine, Medical genomics, 030217 neurology & neurosurgery
Abstract: Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.
Published: 2021

39. Lessons Learned From Neuroimaging Studies of Copy Number Variants: A Systematic Review

Author: Borja Rodriguez-Herreros, Ida E Sønderby, Clara A. Moreau, Sandra Martin-Brevet, Bogdan Draganski, Claudia Modenato, Sébastien Jacquemont, Kuldeep Kumar, University of Lausanne (UNIL), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Sainte Justine [Montréal], Université de Montréal (UdeM), Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Oslo University Hospital [Oslo], University of Oslo (UiO), This work 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 (Grant No. CIHR_400528 [to SJ]), the Institute of Data Valorization through the Canada First Research Excellence Fund, and the Healthy Brains for Healthy Lives through the Canada First Research Excellence Fund. SJ is a recipient of a Canada Research Chair in neurodevelopmental disorders and a chair from the Jeanne et Jean Louis Levesque Foundation. CM was supported by a doc.mobility grant provided by the Swiss National Science Foundation. KK was supported by the Institute of Data Valorization Postdoctoral Fellowship program through the Canada First Research Excellence Fund. BD is supported by the Swiss National Science Foundation, Switzerland (NCCR Synapsy, project Grant Nos. 32003B_135679, 32003B_159780, 324730_192755, and CRSK-3_190185) and the Roger De Spoelberch and Leenaards Foundations. IES was supported by the South-Eastern Norway Regional Health Authority (Grant No. 2020060) and received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant No. 847776 (CoMorMent), the Research Council of Norway (Grant No. 223273), and the Kristian Gerhard Jebsen Stiftelsen (Grant No. SKGJ-MED-021)., European Project: 847776,H2020-SC1-2019-Two-Stage-RTD,CoMorMent(2020), Université de Lausanne = University of Lausanne (UNIL), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, DNA Copy Number Variations, Autism Spectrum Disorder, Autism, Structural imaging, Neuroimaging, Biology, Gene dosage, MESH: Magnetic Resonance Imaging, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Copy-number variation, MESH: Neuroimaging, Biological Psychiatry, Genetics, MESH: Autism Spectrum Disorder, Copy number variants, MESH: Humans, medicine.diagnostic_test, [SCCO.NEUR]Cognitive science/Neuroscience, Brain morphometry, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, MESH: Schizophrenia, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, Schizophrenia, MESH: DNA Copy Number Variations, Psychiatric disorders, 030217 neurology & neurosurgery
Abstract: International audience; Pathogenic copy number variants (CNVs) and aneuploidies alter gene dosage and are associated with neurodevelopmental psychiatric disorders such as autism spectrum disorder and schizophrenia. Brain mechanisms mediating genetic risk for neurodevelopmental psychiatric disorders remain largely unknown, but there is a rapid increase in morphometry studies of CNVs using T1-weighted structural magnetic resonance imaging. Studies have been conducted one mutation at a time, leaving the field with a complex catalog of brain alterations linked to different genomic loci. Our aim was to provide a systematic review of neuroimaging phenotypes across CNVs associated with developmental psychiatric disorders including autism and schizophrenia. We included 76 structural magnetic resonance imaging studies on 20 CNVs at the 15q11.2, 22q11.2, 1q21.1 distal, 16p11.2 distal and proximal, 7q11.23, 15q11-q13, and 22q13.33 (SHANK3) genomic loci as well as aneuploidies of chromosomes X, Y, and 21. Moderate to large effect sizes on global and regional brain morphometry are observed across all genomic loci, which is in line with levels of symptom severity reported for these variants. This is in stark contrast with the much milder neuroimaging effects observed in idiopathic psychiatric disorders. Data also suggest that CNVs have independent effects on global versus regional measures as well as on cortical surface versus thickness. Findings highlight a broad diversity of regional morphometry patterns across genomic loci. This heterogeneity of brain patterns provides insight into the weak effects reported in magnetic resonance imaging studies of cognitive dimension and psychiatric conditions. Neuroimaging studies across many more variants will be required to understand links between gene function and brain morphometry.
Published: 2021

40. 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

41. LMT USV Toolbox, a Novel Methodological Approach to Place Mouse Ultrasonic Vocalizations in Their Behavioral Contexts—A Study in Female and Male C57BL/6J Mice and in Shank3 Mutant Females

Author: De Chaumont, Fabrice, Lemière, Nathalie, Coqueran, Sabrina, Bourgeron, Thomas, Ey, Elodie, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), This work was partially funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, the Cognacq-Jay Foundation, the Conny-Maeva Foundation, the ERANET-NEURON ALTRUISM program, the Agence Nationale de la Recherche through grant number ANR-10-LABX-62-IBEID, France-BioImaging infrastructure through grant number ANR-10-INBS-04 and the INCEPTION program through grant number ANR-16-CONV-0005, the Centre National de la Recherche Scientifique, the University Paris Diderot, the BioPsy Labex, and the Foundation for Medical Research (Equipe DEQ20130326488). This study also benefited from the financial support of GIS 'Autisme et Troubles du Neuro-Développement'., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: mouse model, [SDV.BA]Life Sciences [q-bio]/Animal biology, Cognitive Neuroscience, autism, Neurosciences. Biological psychiatry. Neuropsychiatry, Behavioral Neuroscience, Neuropsychology and Physiological Psychology, age, Shank3, sex, social behavior analysis, mouse, RC321-571, ultrasonic vocalization (USV)
Abstract: International audience; Ultrasonic vocalizations (USVs) are used as a phenotypic marker in mouse models of neuropsychiatric disorders. Nevertheless, current methodologies still require time-consuming manual input or sound recordings clean of any background noise. We developed a method to overcome these two restraints to boost knowledge on mouse USVs. The methods are freely available and the USV analysis runs online at https://usv.pasteur.cloud . As little is currently known about usage and structure of ultrasonic vocalizations during social interactions over the long-term and in unconstrained context, we investigated mouse spontaneous communication by coupling the analysis of USVs with automatic labeling of behaviors. We continuously recorded during 3 days undisturbed interactions of same-sex pairs of C57BL/6J sexually naive males and females at 5 weeks and 3 and 7 months of age. In same-sex interactions, we observed robust differences between males and females in the amount of USVs produced, in the acoustic structure and in the contexts of emission. The context-specific acoustic variations emerged with increasing age. The emission of USVs also reflected a high level of excitement during social interactions. We finally highlighted the importance of studying long-term spontaneous communication by investigating female mice lacking Shank3 , a synaptic protein associated with autism. While the previous short-time constrained investigations could not detect USV emission abnormalities, our analysis revealed robust differences in the usage and structure of the USVs emitted by mutant mice compared to wild-type female pairs.
Published: 2021
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42. Fever during pregnancy as a risk factor for neurodevelopmental disorders: results from a systematic review and meta-analysis

Author: Pierre Gressens, Michelle Rosenzwajg, Hugo Peyre, Stephanie Antoun, Pierre Ellul, Richard Delorme, David Klatzmann, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), King‘s College London, 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), Gestionnaire, HAL Sorbonne Université 5, Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), INSERM, UMR-S 959 (Immunology-immunopathology-immunotherapy (I3)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Pediatrics, medicine.medical_specialty, Offspring, Autism, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Immunology, Maternal Fever, Mothers, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, Pregnancy, Risk Factors, 030225 pediatrics, Maternal immune activation, Humans, Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Risk factor, Child, RC346-429, Molecular Biology, Children, business.industry, Research, Odds ratio, medicine.disease, 3. Good health, Pregnancy Complications, Pregnancy Trimester, First, Psychiatry and Mental health, Neurodevelopmental Disorders, Meta-analysis, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Gestation, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, Developmental Biology, Cohort study
Abstract: Background Fever during pregnancy is a relatively common and most often trivial event. However, under specific conditions, it could affect significantly fetal brain development. Few studies, with inconsistent results, investigated whether fever, regardless the pathogen, could represent a risk factor for neurodevelopmental disorders (NDD) in the offspring. We aimed to explore further this question by performing a systematic review and meta-analysis. Methods Peer-reviewed studies exploring the occurrence of NDD in offspring after a fetal exposure to maternal fever were included. We specifically considered the impact of fever severity and duration, taking into consideration some confounding variables such as the use of antipyretic during pregnancy, the trimester in which the fever arose, the maternal age or smoking at time of gestation. MEDLINE, EMBASE, PsycINFO, Cochrane and Web of Science were searched without language restriction. PRISMA recommendations were followed. Odds ratio (OR) were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using random-effects meta-regression analysis. (PROSPERO CRD42020182801). Results We finally considered ten studies gathering a total of 10,304 children with NDD. Among them, 1394 were exposed to fever during pregnancy. The selected studies were divided into 5 case–control studies and 5 cohort studies. Maternal exposure to fever during pregnancy increased the risk of NDD in offspring with an OR of 1.24 [95% CI: 1.12–1.38]. Secondary analysis revealed an increased risk for NDD when fever occurred during the first trimester of gestation [OR 1.13–95% CI: 1.02–1.26]. Limitations We excluded studies that considered infections with no evidence of fever. Another potential limitation may be the possible heterogeneity between study designs (cohorts and case–control). Conclusion Additional evidence supported the association between fever during pregnancy and increased risk for NDD in offspring. Careful monitoring should be considered for children born from mothers with a febrile episode during pregnancy (specifically during the first trimester).
Published: 2021

43. Discriminant value of repetitive behaviors in families with autism spectrum disorder and obsessional compulsive disorder probands

Author: Daniel Umbricht, Manuel Bouvard, Frédérique Amsellem, Marion Leboyer, Myriam Ly-Le Moal, Anita Beggiato, Lorraine Murtagh, Richard Delorme, Thomas Bourgeron, Aline Lefebvre, Alicia Cohen, Christopher H. Chatham, Anouck Amestoy, Anna Maruani, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Centre Ressources Autisme et Troubles du Développement (CRA), Hôpital Charles Perrens, UFR Sciences médicales 3 [Bordeaux], Laboratoire Roche [Boulogne-Billancourt], Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Fondation FondaMental [Créteil], Pôle de psychiatrie et d'addictologie des Hôpitaux Universitaires Henri-Mondor [Créteil], Centre hospitalier universitaire Henri-Mondor [Créteil], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This study is a part of clinical trial C07-33 sponsored by INSERM. It was financially supported by the funding of the Institut Pasteur, INSERM, the Fondation FondaMental, the APHP, the DHU Protect, the Fondation de France, the Labex BioPsy, the Fondation pour la Recherche Médicale and by the Roche Institute for Research and Translational Medicine, of the Investissements d'Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02, ANR-10-COHO-10-01, ANR-12-SAMA-0014, by the French National Center for Scientific Research (CNRS)., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-COHO-0010,Psy-COH,FondaMental-Cohortes(2010), ANR-12-SAMA-0014,AutoMobil,Encéphalite avec autoanticorps anti-récepteurs synaptiques : un nouveau modèle de troubles psychotiques(2012), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre hospitalier Charles Perrens [Bordeaux], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)
Subjects: Proband, Obsessive-Compulsive Disorder, Autism Spectrum Disorder, phenotype, Population, heritability, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, Cognition, Intellectual disability, mental disorders, medicine, Humans, 0501 psychology and cognitive sciences, Expressivity (genetics), education, habits, Genetics (clinical), education.field_of_study, neurodevelopment, business.industry, General Neuroscience, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, Family aggregation, medicine.disease, Autism spectrum disorder, Autism, Neurology (clinical), business, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology
Abstract: International audience; Repetitive behaviors (RB) represent a wide spectrum of symptoms ranging from sensory-motor stereotypies to complex cognitive rituals, frequently dichotomized as low- and high-order sub-groups of symptoms. Even though these subgroups are considered as phenomenologically distinct in autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD), brain imaging and genetic studies suggest that they have common mechanisms and pathways. This discrepancy may be explained by the frequent intellectual disability reported in ASD, which blurs the RB expressivity. Given the high heritability of RB, that is, the diversity of symptoms expressed in the relatives are dependent on those expressed in their probands, we hypothesize that if RB expressed in ASD or OCD are two distinct entities, then the RB expressed in relatives will also reflect these two dimensions. We thus conduct a linear discriminant analysis on RB in both the relatives of probands with ASD and OCD and subjects from the general population (n = 1023). The discriminant analysis results in a classification of 81.1% of the controls (p
Published: 2021

44. Dissecting autism and schizophrenia through neuroimaging genomics

Author: Clara Moreau, Armin Raznahan, Sébastien Jacquemont, M. Mallar Chakravarty, Pierre Bellec, Paul M. Thompson, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Montréal (UdeM), Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal (CRIUGM), National Institute of Mental Health (NIMH), Centre de recherche de l'Institut universitaire de gériatrie de Montreal (CRIUGM), Douglas Mental Health University Institute, McGill University = Université McGill [Montréal, Canada], Laboratory of Neuro Imaging [Los Angeles] (LONI), University of California [Los Angeles] (UCLA), University of California-University of California, This research was supported by the Brain Canada Multi investigator research initiative (MIRI), funds from the Institute of Data Valorization (IVADO). S.J. is supported by the Canadian Institute of Health Research CIHR_400528 and the 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. P.B. is a fellow (‘Chercheur boursier Junior 2’) of the ‘Fonds de recherche du Québec—Santé’., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and University of California (UC)-University of California (UC)
Subjects: 0301 basic medicine, Autism Spectrum Disorder, autism, Genomics, Disease, Biology, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, medicine, Humans, Copy-number variation, MESH: Neuroimaging, Medical diagnosis, Review Articles, MESH: Autism Spectrum Disorder, neuroimaging, MESH: Humans, AcademicSubjects/SCI01870, MESH: Genomics, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, MESH: Schizophrenia, schizophrenia, 030104 developmental biology, Autism spectrum disorder, Schizophrenia, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Autism, AcademicSubjects/MED00310, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery, copy number variants
Abstract: Neuroimaging genomic studies of autism spectrum disorder and schizophrenia have mainly adopted a ‘top-down’ approach, beginning with the behavioural diagnosis, and moving down to intermediate brain phenotypes and underlying genetic factors. Advances in imaging and genomics have been successfully applied to increasingly large case-control studies. As opposed to diagnostic-first approaches, the bottom-up strategy begins at the level of molecular factors enabling the study of mechanisms related to biological risk, irrespective of diagnoses or clinical manifestations. The latter strategy has emerged from questions raised by top-down studies: why are mutations and brain phenotypes over-represented in individuals with a psychiatric diagnosis? Are they related to core symptoms of the disease or to comorbidities? Why are mutations and brain phenotypes associated with several psychiatric diagnoses? Do they impact a single dimension contributing to all diagnoses? In this review, we aimed at summarizing imaging genomic findings in autism and schizophrenia as well as neuropsychiatric variants associated with these conditions. Top-down studies of autism and schizophrenia identified patterns of neuroimaging alterations with small effect-sizes and an extreme polygenic architecture. Genomic variants and neuroimaging patterns are shared across diagnostic categories suggesting pleiotropic mechanisms at the molecular and brain network levels. Although the field is gaining traction; characterizing increasingly reproducible results, it is unlikely that top-down approaches alone will be able to disentangle mechanisms involved in autism or schizophrenia. In stark contrast with top-down approaches, bottom-up studies showed that the effect-sizes of high-risk neuropsychiatric mutations are equally large for neuroimaging and behavioural traits. Low specificity has been perplexing with studies showing that broad classes of genomic variants affect a similar range of behavioural and cognitive dimensions, which may be consistent with the highly polygenic architecture of psychiatric conditions. The surprisingly discordant effect sizes observed between genetic and diagnostic first approaches underscore the necessity to decompose the heterogeneity hindering case-control studies in idiopathic conditions. We propose a systematic investigation across a broad spectrum of neuropsychiatric variants to identify putative latent dimensions underlying idiopathic conditions. Gene expression data on temporal, spatial and cell type organization in the brain have also considerable potential for parsing the mechanisms contributing to these dimensions’ phenotypes. While large neuroimaging genomic datasets are now available in unselected populations, there is an urgent need for data on individuals with a range of psychiatric symptoms and high-risk genomic variants. Such efforts together with more standardized methods will improve mechanistically informed predictive modelling for diagnosis and clinical outcomes., Moreau et al. review advances and roadblocks in neuroimaging genomic studies of autism and schizophrenia. They propose combining diagnosis-first (‘top-down’) and gene-first (‘bottom-up’) strategies to parse out the contribution of genes and biological processes to dimensions involved in these psychiatric conditions.
Published: 2021

45. Polygenic scores for intelligence, educational attainment and schizophrenia are differentially associated with core autism features, IQ, and adaptive behaviour in autistic individuals

Author: Warrier, Varun, Leblond, Claire, Cliquet, Freddy, Leap, Aims-2-Trials, Bourgeron, Thomas, Baron-Cohen, Simon, University of Cambridge [UK] (CAM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), V.W. is funded by St. Catharines College, Cambridge. This study was funded by grants to SBC from the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Templeton World Charity Foundation, and to T.B. from the Institut Pasteur, the CNRS, The Bettencourt-Schueller and the Cognacq-Jay Foundations, the APHP and the Universite de Paris. SBC was funded by the Autism Research Trust, the Wellcome Trust, the Templeton World Charitable Foundation, and the NIHR Biomedical Research Centre in Cambridge, during the period of this work., List of authors and their affiliations for the EU-AIMS LEAP group : KCL: Dr Antonia San Jose Caceres, Hannah Hayward, Daisy Crawley, Jessica Faulkner, Jessica Sabet, Claire Ellis, Bethany Oakley, Dr. Eva Loth, Prof. Tony Charman, Prof. Declan Murphy, University of Cambridge: Dr. Rosemary Holt , Jack Waldman, Jessica Upadhyay, Nicola Gunby, Dr. Meng-Chuan Lai, Gwilym Renouf, Dr. Amber Ruigrok, Emily Taylor, Dr. Hisham Ziauddeen, Dr. Julia Deakin, Professor Simon Baron-Cohen, UMC Utrecht: Sara Ambrosino di Bruttopilo, Sarai van Dijk, Yvonne Rijks, Tabitha Koops, Miriam Douma, Alyssia Spaan, Iris Selten, Maarten Steffers, Anna Ver Loren van Themaat, Central Institute of Mental Health Mannheim: Dr. Nico Bast, Dr. Sarah Baumeister, Radboudumc: Dr Larry O’Dwyer, Carsten Bours, Annika Rausch Dr. Daniel von Rhein, Ineke Cornelissen, Yvette de Bruin, Maartje Graauwmans, Karolinska Institutet: Elzbieta Kostrzewa, Elodie Cauvet, Dr. Kristiina Tammimies, Rouslan Sitnikow, Institut Pasteur: Dr. Guillaume Dumas, Dr. Yang-Min Kim, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Posté sur medRxiv le 24 juillet 2020.; ImportanceSchizophrenia, educational attainment, and intelligence are all genetically correlated with autism. However, autism is a complex condition, with several different core (such as social communication difficulties and repetitive and restricted behaviour) and associated features (such as IQ and adaptive behaviour) contributing to the underlying heterogeneity. It is unknown to what extent polygenic scores (PGS) for these three phenotypes are associated with the core and associated autism features.ObjectiveTo investigate the association of PGS for intelligence, educational attainment and schizophrenia on core autism features, IQ and adaptive behaviour in autistic individuals. To further investigate the effects of stratifying by sex and IQ on these associations.DesignPGS association for the three phenotypes with 12 different autism core and associated features in three cohorts followed by meta-analysis. We additionally conducted sensitivity analyses by stratifying for sex and IQ.Settings :Three cross-sectional, multi-centre cohorts comprising autistic with genotype data, and phenotypic information.ParticipantsAutistic individuals (total N: 2,512 – 3,681) from three different cohorts: Simons Simplex Collection (Nmax = 2,233), Autism Genetic Research Exchange (Nmax = 1,200), and AIMS-2- TRIALS LEAP (Nmax = 262)Main outcome measuresAssociation of PGS for intelligence, educational attainment, and schizophrenia with core autism features, measures of intelligence, and adaptive behaviour in autistic individualsResultsWe identified a similar pattern of correlation among core and associated autism features across all three cohorts. Cluster analyses of these features identified two broad clusters – one consisting of the core features, and another consisting of IQ and adaptive behaviour. PGS for intelligence were only associated with measures of intelligence and adaptive behaviour (e.g. for full-scale IQ, Beta = 0.08, 95%CI = 0.11 – 0.04) for PGS for educational attainment were associated for measures of intelligence, adaptive behaviour, and additionally, non-verbal communication as measured by ADI – a core-autism feature (e.g. for full-scale IQ, Beta = 0.05, 95%CI = 0.08 – 0.02; for ADI non-verbal communication, Beta = 0.05, 95%CI = 0.09 – 0.01). Finally, PGS for schizophrenia were associated with two core autism features: restricted and repetitive behaviour and verbal communication difficulties as measured by the ADI-R (e.g. for ADI restricted and repetitive behaviour: Beta = 0.06, 95%CI = 0.09 – 0.02). Most of these associations were also significant when restricting it to males only or to individuals with IQ > 70. We find limited evidence for heterogeneity between cohorts.Conclusion and relevanceWe identify specific and different patterns of association between PGS for the three phenotypes and core and associated autism features. This provides greater resolution into the shared genetics between autism and the three phenotypes, and suggests one method to investigate heterogeneity in autism and co-occurring conditions.
Published: 2021

46. Towards a gene-level map of resilience to genetic variants associated with autism

Author: Rolland, Thomas, Cliquet, Freddy, Anney, Richard, Traut, Nicolas, Mathieu, Alexandre, Huguet, Guillaume, Leblond, Claire, Douard, Elise, Amsellem, Frédérique, Malesys, Simon, Maruani, Anna, Toro, Roberto, Packer, Alan, Chung, Wendy, Jacquemont, Sébastien, Delorme, Richard, Bourgeron, Thomas, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Cardiff University, Centre de Recherches Interdisciplinaires (CRI), Université de Paris (UP), Université de Montréal (UdeM), Centre de recherche du CHU Sainte-Justine [Montreal], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Simons Foundation, Columbia University Medical Center (CUMC), Columbia University [New York], This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Eranet-Neuron (ALTRUISM), the GenMed Labex, AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the European Union’s Horizon 2020 research and innovative program CANDY under grant agreement No 847818., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Université Paris Cité (UPC)
Subjects: genetic structures, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], mental disorders, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], behavioral disciplines and activities
Abstract: Posté sur medRxiv le 6 mars 2021.; While over 100 genes are now significantly associated with autism spectrum disorders (ASD), the penetrance of the variants affecting these genes remains poorly understood. Here, we quantified the prevalence of rare loss-of-function (LoF) mutations affecting 156 genes robustly associated with ASD (SPARK genes) using genetic data from more than 10,000 individuals with ASD and 100,000 undiagnosed individuals. We then investigated the clinical, brain imaging and genetic profiles of individuals heterozygous for these rare deleterious variants who were not diagnosed with ASD. These “resilient” individuals, observed in less than 1% of the general population, were equally distributed among males and females, but displayed low polygenic scores for ASD compared to LoF heterozygotes diagnosed with ASD. The interplay between rare and common variants may therefore contribute to the clinical profiles of the individuals carrying LoF in genes associated with ASD.
Published: 2021

47. Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

Author: Meng-Chuan Lai, Elena Maria Busuoli, Antonio M. Persico, Bonnie Auyeung, Eva Loth, Sarah Durston, Andreas Meyer-Lindenberg, Sven Bölte, Carolin Moessnang, Stavros Trakoshis, Marianne Oldehinkel, Prantik Kundu, Steve C.R. Williams, Jan K. Buitelaar, Sarah Baumeister, Tony Charman, Michael V. Lombardo, Isotta Landi, Richard A. I. Bethlehem, Rosemary Holt, Veronica Mandelli, Christine Ecker, Natasha Bertelsen, Julian Tillmann, Declan G. Murphy, Christian F. Beckmann, Jakob Seidlitz, Eleonora Satta, Mark H. Johnson, Will Spooren, Simon Baron-Cohen, Guillaume Dumas, Luke Mason, Emily J.H. Jones, Thomas Bourgeron, Istituto Italiano di Tecnologia (IIT), University of Trento [Trento], University of Cambridge [UK] (CAM), Children’s Hospital of Philadelphia (CHOP ), University of Pennsylvania, University of Cyprus [Nicosia] (UCY), University of Edinburgh, King‘s College London, 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), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Karolinska Institutet [Stockholm], Stockholm Health Care Services (SLSO), Curtin University [Perth], Planning and Transport Research Centre (PATREC), University Medical Center [Utrecht], Goethe-Universität Frankfurt am Main, University of London [London], Monash University [Melbourne], University of Messina, Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), University of Vienna [Vienna], Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Centre for Addiction and Mental Health [Toronto] (CAMH), The Hospital for sick children [Toronto] (SickKids), University of Toronto, National Taiwan University [Taiwan] (NTU), This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 755816 (ERC Starting Grant to MVL). This work was also supported by EU-AIMS and EU AIMS-2-TRIALS, which both received support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115300 and the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 777394, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (Grant No. FP7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and from Autism Speaks, Autistica and the Simons Foundation for Autism Research Initiative. The views expressed are those of the author(s) and not necessarily those of the IMI 2JU. This work was also supported by the Netherlands Organization for Scientific Research through Vidi grants (Grant No. 864.12.003 [to CFB]), from the FP7 (Grant Nos. 602805) (AGGRESSOTYPE) (to JKB), 603016 (MATRICS), and 278948 (TACTICS), and from the European Community’s Horizon 2020 Programme (H2020/2014–2020) (Grant Nos. 643051 [MiND] and 642996 (BRAINVIEW). This work received funding from the Wellcome Trust UK Strategic Award (Award No. 098369/Z/12/Z) and from the National Institute for Health Research Maudsley Biomedical Research Centre (to DGMM). M-CL was supported by the Academic Scholars Award from the Department of Psychiatry, University of Toronto, the Slaight Family Child and Youth Mental Health Innovation Fund from the CAMH Foundation, the Ontario Brain Institute via the Province of Ontario Neurodevelopmental Disorders (POND) Network (IDS-I l-02), the Canadian Institutes of Health Research Sex and Gender Science Chair (GSB 171373), and the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario (CAM-20-004). R.A.I.B acknowledges research support by the Autism Research Trust and a British Academy Fellowship (PF2\180017). MHJ, TC, and EJHJ acknowledge support from a UK MRC Programme Grant., the EU-AIMS LEAP group : Jumana Ahmad, Sara Ambrosino, Bonnie Auyeung, Tobias Banaschewski, Simon Baron-Cohen, Sarah Baumeister, Christian F. Beckmann, Sven Bölte, Thomas Bourgeron, Carsten Bours, Michael Brammer, Daniel Brandeis, Claudia Brogna, Yvette de Bruijn, Jan K. Buitelaar, Bhismadev Chakrabarti, Tony Charman, Chris Chatham, Ineke Cornelissen, Daisy Crawley, Flavio Dell’Acqua, Guillaume Dumas, Sarah Durston, Christine Ecker, Jessica Faulkner, Vincent Frouin, Pilar Garcés, David Goyard, Lindsay Ham, Hannah Hayward, Joerg Hipp, Rosemary J. Holt, Mark H. Johnson, Emily J. H. Jones, Prantik Kundu, Meng-Chuan Lai, Xavier Liogier D’ardhuy, Michael V. Lombardo, Eva Loth, David J. Lythgoe, René Mandl, Andre Marquand, Luke Mason, Maarten Mennes, Andreas Meyer-Lindenberg, Carolin Moessnang, Nico Mueller, Declan G. M. Murphy, Bethany Oakley, Laurence O’Dwyer, Marianne Oldehinkel, Bob Oranje, Gahan Pandina, Antonio M. Persico, Barbara Ruggeri, Amber N. V. Ruigrok, Jessica Sabet, Roberto Sacco, Antonia San José Cáceres, Emily Simonoff, Will Spooren, Julian Tillmann, Roberto Toro, Heike Tost, Jack Waldman, Steve C. R. Williams, Caroline Wooldridge & Marcel P. Zwiers, European Project: 0755816(2008), European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), European Project: 602805,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,AGGRESSOTYPE(2013), European Project: 603016,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,MATRICS(2014), European Project: 278948,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,TACTICS(2012), European Project: 643051,H2020,H2020-MSCA-ITN-2014,MiND(2015), European Project: 642996,H2020,H2020-MSCA-ITN-2014,BRAINVIEW(2015), University of Pennsylvania [Philadelphia], University of Cyprus (UCY), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Universität Heidelberg [Heidelberg], Bethlehem, Richard A I [0000-0002-0714-0685], Seidlitz, Jakob [0000-0002-8164-7476], Bourgeron, Thomas [0000-0001-8164-9220], Charman, Tony [0000-0003-1993-6549], Persico, Antonio M [0000-0001-8910-4479], Lombardo, Michael V [0000-0001-6780-8619], Apollo - University of Cambridge Repository, and Bethlehem, Richard AI [0000-0002-0714-0685]
Subjects: Male, 0301 basic medicine, Autism Spectrum Disorder, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Medicine (miscellaneous), MESH: Magnetic Resonance Imaging, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, MESH: Child, Neural Pathways, Biology (General), Child, MESH: Autism Spectrum Disorder, MESH: Child Behavior Disorders, Communication, 220 Statistical Imaging Neuroscience, Hyperconnectivity, Autism spectrum disorders, Magnetic Resonance Imaging, Autism spectrum disorder, Female, MESH: Communication, General Agricultural and Biological Sciences, MESH: Stereotyped Behavior, QH301-705.5, autism spectrum disorders, Child Behavior Disorders, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Neuroimaging, mental disorders, medicine, Biological neural network, Humans, Association (psychology), MESH: Neurodevelopmental Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MESH: Humans, Resting state fMRI, Genetic heterogeneity, MESH: Neural Pathways, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, MESH: Male, 030104 developmental biology, Neurodevelopmental Disorders, Autism, Stereotyped Behavior, Neuroscience, MESH: Female, 030217 neurology & neurosurgery
Abstract: Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry., Natasha Bertelsen et al. develop a computational model to categorize patients with autism spectrum disorder (ASD) into distinct subgroups, based on social-communicative or restricted repetitive behaviors. By integrating publicly available neuroimaging and genetic data, they report neural and molecular signatures in two of these subgroups, altogether highlighting subtle differences in neural circuitry and genomic networks that could underlie phenotypic differences among ASD patients.
Published: 2021

48. Operative list of genes associated with autism and neurodevelopmental disorders based on database review

Author: Richard Delorme, Thuy-Linh Le, Simon Malesys, Thomas Bourgeron, Claire S. Leblond, Thomas Rolland, Freddy Cliquet, Anne-Claude Tabet, 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), Hôpital Robert Debré, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the Fundamental Foundation, OdyseeRe, The Roger de Spoelberch Foundation, ERANET-Neuron (ALTRUISM), AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394, the Human Brain Project and the Inception program (Investissement d'Avenir grant ANR-16-CONV-0005)., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP)
Subjects: Genetic diagnostic, High-confidence neurodevelopmental disorder genes, Developmental Disabilities, Autism, Biology, computer.software_genre, medicine.disease_cause, 03 medical and health sciences, Cellular and Molecular Neuroscience, Databases, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Intellectual disability, Databases, Genetic, medicine, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Protein Interaction Maps, Autistic Disorder, Molecular Biology, Gene, 030304 developmental biology, 0303 health sciences, Mutation, Database, Neurodevelopmental disorders, Cell Biology, Human brain, medicine.disease, Omics, Phenotype, 3. Good health, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Identification (biology), Fetal brain expression & synaptic function, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery
Abstract: International audience; The genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated with conditions such as intellectual disability and autism. The functional roles of these genes are currently studied to uncover the biological mechanisms influencing the clinical outcome of the mutation carriers. To integrate the data, several databases and curated gene lists have been generated. Here, we provide an overview of the main databases focusing on the genetics of NDD, that are widely used by the medical and scientific communities, and extract a list of high confidence NDD genes (HC-NDD). This gene set can be used as a first filter for interpreting large scale omics dataset or for diagnostic purposes. Overall HC-NDD genes (N = 1,586) are expressed at very early stages of fetal brain development and enriched in several biological pathways such as chromosome organization, cell cycle, metabolism and synaptic function. Among those HC-NDD genes, 204 (12,9%) are listed in the synaptic gene ontology SynGO and are enriched in genes expressed after birth in the cerebellum and the cortex of the human brain. Finally, we point at several limitations regarding the relatively poor standardized information available, especially on the carriers of the mutations. Progress on the phenotypic characterization and genetic profiling of the carriers will be crucial to improve our knowledge on the biological mechanisms and on risk and protective factors for NDD.
Published: 2021

49. Long-term outcome in neuroZika

Author: Quentin Lobjois, Pascale Poullain, Etienne C. Hirsch, Guillaume Thiery, Françoise Lazarini, Fatiha Najioullah, Jean-Louis Fergé, Emmanuel Roze, Sébastien Breurec, Anne-Charlotte Savidan, Benoit Tressières, Annie Lannuzel, Eavan McGovern, Aissatou Signate, André Cabié, Ruddy Valentino, Yoann Madec, Pierre-Marie Lledo, Benoît Rozé, Raymond Césaire, Cécile Herrmann, Hirsch, Etienne, Service de Neurologie [CHU Pointe à Pitre], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU de la Martinique [Fort de France], Centre d'investigation clinique Antilles-Guyane (CIC - Antilles Guyane), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de la Martinique [Fort de France]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur de la Guadeloupe, Réseau International des Instituts Pasteur (RIIP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Perception et Mémoire - Perception and Memory, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université des Antilles (UA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de la Martinique [Fort de France]-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Institut Pasteur [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Perception et Mémoire / Perception and Memory, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, West Indies, medicine.medical_treatment, Guillain-Barre Syndrome, [SCCO]Cognitive science, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Interquartile range, Epidemiology, medicine, Humans, Encephalitis, Viral, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030212 general & internal medicine, Child, Encephalomyelitis, Stroke, Aged, Mechanical ventilation, Guillain-Barre syndrome, Zika Virus Infection, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Infant, Odds ratio, Middle Aged, Prognosis, medicine.disease, Respiration, Artificial, Cranial Nerve Diseases, 3. Good health, Hospitalization, Treatment Outcome, Child, Preschool, RNA, Viral, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery, Encephalitis
Abstract: ObjectiveTo characterize the full spectrum, relative frequency, and prognosis of the neurologic manifestations in Zika virus (ZIKV) postnatal infection.MethodsWe conducted an observational study in consecutive ZIKV-infected patients presenting with neurologic manifestations during the French West Indies 2016 outbreak.ResultsEighty-seven patients, including 6 children, were enrolled. Ninety-five percent of all cases required hospitalization. Guillain-Barré syndrome was the most frequent manifestation (46.0%) followed by encephalitis or encephalomyelitis (20.7%), isolated single or multiple cranial nerve palsies (9.2%), other peripheral manifestations (6.9%), and stroke (1.1%). Fourteen patients (16.1%), including one child, developed a mixed disorder involving both the central and peripheral nervous system. Mechanical ventilation was required in 21 cases, all of whom had ZIKV RNA in at least one biological fluid. Two adult patients died due to neuroZika. Clinical follow-up (median 14 months; interquartile range, 13–17 months) was available for 76 patients. Residual disability (modified Rankin Scale score ≥2) was identified in 19 (25.0%) patients; in 6 cases (7.9%), disability was severe (modified Rankin Scale score ≥4). Among patients with ZIKV RNA detected in one biological fluid, the risk of residual disability or death was higher (odds ratio 9.19; confidence interval 1.12–75.22; p = 0.039).ConclusionsNeuroZika spectrum represents a heterogeneous group of clinical neurologic manifestations. During an outbreak, clinicians should consider neuroZika in patients presenting with cranial nerve palsies and a mixed neurologic disorder. Long-term sequelae are frequent in NeuroZika. ZIKV reverse-transcription PCR status at admission can inform prognosis and should therefore be taken into consideration in the management of hospitalized patients.
Published: 2019

50. Sex Differences Along the Autism Continuum: A Twin Study of Brain Structure

Author: Janina Neufeld, Roberto Toro, Katell Mevel, Annelies van't Westeinde, Sven Bölte, Ralf Kuja-Halkola, Elodie Cauvet, Karolinska Institutet [Stockholm], Stockholm County Council, 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), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Medical Epidemiology and Biostatistics (MEB), Laboratoire de psychologie du développement et de l'éducation de l'enfant (LaPsyDÉ - UMR 8240), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Curtin University [Perth], Planning and Transport Research Centre (PATREC), The study was funded by the Swedish Research Council, Vinnova, Formas, FORTE, the Swedish Brain foundation (Hjärnfonden), Stockholm Brain Institute, Autism and Asperger Association Stockholm, Queen Silvia Jubilee Fund, Solstickan Foundation, PRIMA Child and Adult Psychiatry, the Pediatric Research Foundation at Astrid Lindgren Children’s Hospital, Sällskapet Barnavård, Jerring Foundation, the Swedish Order of Freemasons, Kempe–Carlgrenska Foundation, Sunnderdahls Handikappsfond, the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115300), which comprises financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and in-kind contributions from companies belonging to the European Federation of Pharmaceutical Industries and Associations (EU-AIMS)., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], and Gènes, Synapses et Cognition
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, neuroanatomy, Cognitive Neuroscience, Monozygotic twin, autism spectrum disorder, Audiology, Biology, 050105 experimental psychology, Developmental psychology, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, biological sex, Twins, Dizygotic, medicine, Humans, Genetic Predisposition to Disease, 0501 psychology and cognitive sciences, Child, Sex Characteristics, Social communication, Confounding, 05 social sciences, Brain morphometry, Brain, Twins, Monozygotic, Original Articles, twins, medicine.disease, Twin study, medicine.anatomical_structure, Autism spectrum disorder, Brain size, Autism, Female, Gene-Environment Interaction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], autistic traits, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Sex characteristics, Neuroanatomy
Abstract: International audience; Females might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N = 148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area, and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture associated with autistic traits. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.
Published: 2018

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