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16 results on '"ANR-10-LABX-0013,GENMED,Medical Genomics(2010)"'

1. Association of ABO blood groups with venous thrombosis recurrence in middle-aged patients: insights from a weighted Cox analysis dedicated to ambispective design

Author: Gaëlle Munsch, Louisa Goumidi, Astrid van Hylckama Vlieg, Manal Ibrahim-Kosta, Maria Bruzelius, Jean-François Deleuze, Frits R. Rosendaal, Hélène Jacqmin-Gadda, Pierre-Emmanuel Morange, David-Alexandre Trégouët, 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), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and ANR-10-LABX-0013,GENMED,Medical Genomics(2010)
Subjects: Genetic association studies, Epidemiology, Recurrence, Venous thrombosis, Ambispective design, Health Informatics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Survival analysis, ABO blood groups
Abstract: Background In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of time, including both pre- and post-inclusion events in the analyses, generally referred to as relying on an ambispective design, increases the statistical power but may lead to a selection bias. In the field of venous thromboembolism (VT), ABO blood groups have been the subject of extensive research due to their substantial effect on VT risk. However, few studies have investigated their effect on the risk of VT recurrence. Motivated by the study of the association of genetically determined ABO blood groups with VT recurrence, we propose a methodology to include pre-inclusion events in the analysis of ambispective studies while avoiding the selection bias due to mortality. Methods This work relies on two independent cohorts of VT patients, the French MARTHA study built on an ambispective design and the Dutch MEGA study built on a standard prospective design. For the analysis of the MARTHA study, a weighted Cox model was developed where weights were defined by the inverse of the survival probability at the time of data collection about the events. Thanks to the collection of information on the vital status of patients, we could estimate the survival probabilities using a delayed-entry Cox model on the death risk. Finally, results obtained in both studies were then meta-analysed. Results In the combined sample totalling 2,752 patients including 993 recurrences, the A1 blood group has an increased risk (Hazard Ratio (HR) of 1.18, p = 4.2 × 10–3) compared with the O1 group, homogeneously in MARTHA and in MEGA. The same trend (HR = 1.19, p = 0.06) was observed for the less frequent A2 group. Conclusion The proposed methodology increases the power of studies relying on an ambispective design which is frequent in epidemiologic studies about recurrent events. This approach allowed to clarify the association of ABO blood groups with the risk of VT recurrence. Besides, this methodology has an immediate field of application in the context of genome wide association studies.
Published: 2023
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2. 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

3. Common and Rare 5'UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics

Author: Omar Soukarieh, Caroline Meguerditchian, Carole Proust, Dylan Aïssi, Mélanie Eyries, Aurélie Goyenvalle, David-Alexandre Trégouët, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche, Université de Bordeaux, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Admin, Oskar, and Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID
Subjects: Genome wide association analysis (GWAS), [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Non-coding mutations, Open reading frame (ORF), Mendelian disease, Polymorphism, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; High-throughput sequencing (HTS) technologies are revolutionizing the research and molecular diagnosis landscape by allowing the exploration of millions of nucleotide sequences at an unprecedented scale. These technologies are of particular interest in the identification of genetic variations contributing to the risk of rare (Mendelian) and common (multifactorial) human diseases. So far, they have led to numerous successes in identifying rare disease-causing mutations in coding regions, but few in non-coding regions that include introns, untranslated (UTR), and intergenic regions. One class of neglected non-coding variations is that of 5'UTR variants that alter upstream open reading frames (upORFs) of the coding sequence (CDS) of a natural protein coding transcript. Following a brief summary of the molecular bases of the origin and functions of upORFs, we will first review known 5'UTR variations altering upORFs and causing rare cardiovascular disorders (CVDs). We will then investigate whether upORF-affecting single nucleotide polymorphisms could be good candidates for explaining association signals detected in the context of genome-wide association studies for common complex CVDs.
Published: 2022
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4. An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

Author: Razzaq, Misbah, Iglesias, Maria Jesus, Ibrahim-Kosta, Manal, Goumidi, Louisa, Soukarieh, Omar, Proust, Carole, Roux, Maguelonne, Suchon, Pierre, Boland, Anne, Daiain, Delphine, Olaso, Robert, Havervall, Sebastian, Thalin, Charlotte, Butler, Lynn, Deleuze, Jean-François, Odeberg, Jacob, Morange, Pierre-Emmanuel, Trégouët, David-Alexandre, 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), Agence Nationale de la Recherche, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Adult, Male, Proteomics, Science, COVID-19, Receptors, Cell Surface, Polymorphism, Single Nucleotide, Article, Phenotype, Machine learning, Genetics, Humans, Medicine, Female, Genetic Predisposition to Disease, Data integration, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neural Networks, Computer, Pulmonary Embolism, Genome-Wide Association Study
Abstract: International audience; Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10(-7)) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.
Published: 2021
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5. Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition

Author: Dumas, Guillaume, Malesys, Simon, 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), Université de Montréal (UdeM), CHU Sainte Justine [Montréal], This work was supported by the Institut Pasteur, Centre National de la Recherche Scientifique, Paris Diderot University, the Fondation pour la Recherche Médicale (DBI20141231310), the Human Brain Project, the Cognacq-Jay Foundation, the Bettencourt-Schueller Foundation, the Agence Nationale de la Recherche (ANR) (SynPathy), and the Innovative Medicines Initiative 2 [No. 777394]. This research was also supported by the Laboratory of Excellence GENMED (Medical Genomics) Grant No. ANR-10-LABX-0013, Bio-Psy, and by the INCEPTION program ANR-16-CONV-0005, all managed by the ANR part of the Investments for the Future program. G.D. is funded by the Institute for Data Valorization (IVADO), Montreal, and the Fonds de Recherche du Québec (FRQ, 295291, 295289)., We thank J.-P. Changeux, L. Quintana-Murci, E. Patin, G. Laval, B. Arcangioli, D. DiGregorio, L. Bally-Cuif, A. Chedotal, C. Berthelot, H. Roest Crollius, and V. Warrier for advice and comments, and we thank the members of the Human Genetics and Cognitive Functions laboratory for helpful discussions. We also thank C. Gorgolewski, R. Carter, M. Haeussler, M. Verhage, and the SynGO consortium for providing key data sets without which this work would not have been possible., ANR-15-NEUR-0007,SynPathy,Key Determinants of Synaptic Excitation-Inhibition Imbalance in Autism Spectrum Disorders - From Genetic Animal Models to Human Patients(2015), 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), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP)
Subjects: Resource, Evolution, Molecular, Primates, Brain Diseases, Cognition, DNA Repair Enzymes, [SCCO.NEUR]Cognitive science/Neuroscience, Animals, Brain, Humans, Proteins, Selection, Genetic, DNA Damage
Abstract: International audience; The human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N = 11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein-coding genome with recent data sets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism. Among those, a number of DNA damage response genes associated with microcephaly in humans such as BRCA1, NHEJ1, TOP3A, and RNF168 show strong signs of positive selection and might have played a role in human brain size expansion during primate evolution. We also showed that cerebellum granule neurons express a set of genes also presenting signatures of positive selection and that may have contributed to the emergence of fine motor skills and social cognition in humans. This resource is available online and can be used to estimate evolutionary constraints acting on a set of genes and to explore their relative contributions to human traits.
Published: 2021
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6. Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders

Author: Pagan, Cécile, Benabou, Marion, Leblond, Claire, Cliquet, Freddy, Mathieu, Alexandre, Lemière, Nathalie, Goubran-Botros, Hany, Delorme, Richard, Leboyer, Marion, Callebert, Jacques, Bourgeron, Thomas, Launay, Jean-Marie, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Fondation FondaMental [Créteil], 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), 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, Pôle de Psychiatrie [Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital H. Mondor - A. Chenevier, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Psychiatrie Translationnelle (Equipe 15), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Réseau de coopération scientifique en santé mentale, Fondation FondaMental [Créteil]-Fondation FondaMental [Créteil], This work was supported by academic institutions (Institut Pasteur, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Assistance Publique – Hôpitaux de Paris, Université de Paris), academic grants: Agence Nationale de la Recherche (ANR) [ERANET-Neuron Altruism], the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013, charity foundations: Bettencourt-Schueller foundation, FondaMental foundation, Conny-Maeva foundation, Cognacq-Jay foundation., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Réseau de coopération scientifique en santé mentale, Fondation FondaMental [Créteil]-Fondation FondaMental [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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cliquet, Freddy, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Serotonin, Physiology, Autism Spectrum Disorder, Siblings, food and beverages, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorders, Arylsulfotransferase, Article, lcsh:RC321-571, Mice, [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, Genetics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Sulfotransferases, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biomarkers, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD-an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparansulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.
Published: 2021
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7. Mass‐spectrometry analysis of the human pineal proteome during night and day and in autism

Author: Guillaume, Dumas, Hany, Goubran-Botros, Mariette, Matondo, Cécile, Pagan, Cyril, Boulègue, Thibault, Chaze, Julia, Chamot-Rooke, Erik, Maronde, 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), Precision Psychiatry and Social Physiology laboratory [Montreal] (PPHP), CRSN/Faculté de médecine Université de Montréal-CHU Sainte Justine [Montréal], Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Service de Biochimie et de Biologie Moléculaire [AP-HP Hôpital Lariboisière] (Inserm U942), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Anatomy II, Goethe-Universität Frankfurt am Main, This work was supported by the Institut Pasteur, the CNRS, the INSERM, the AP-HP, the University Paris Diderot, the Cognacq-Jay foundation, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Fondation de France, the Conny-Maeva foundation, the Eranet-Neuron ANR (ALTRUISM), and the Labex GenMed and BioPsy. GD is funded by the Institute for Data Valorization (IVADO), Montreal, and the Fonds de recherche du Québec (FRQ)., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), PORTELETTE, Virginie, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, and Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID
Subjects: Proteomics, chaperon proteins, circadian rhythm, Spectrometry, Mass, Electrospray Ionization, endocrine system, Time Factors, antioxidant, Proteome, pineal gland, autism spectrum disorders, autism spectrum disorder, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, energy production, Tandem Mass Spectrometry, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Interaction Maps, Autistic Disorder, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, mass spectrometry, Proteins, Original Articles, mass spectometry, Case-Control Studies, Original Article, hormones, hormone substitutes, and hormone antagonists
Abstract: International audience; The human pineal gland regulates day‐night dynamics of multiple physiological processes, especially through the secretion of melatonin. Using mass spectrometry‐based proteomics and dedicated analysis tools, we identify proteins in the human pineal gland and analyze systematically their variation throughout the day, and, compare these changes in the pineal proteome between control specimens and donors diagnosed with autism. Results reveal diverse regulated clusters of proteins with, among others, catabolic carbohydrate process and cytoplasmic membrane‐bounded vesicle‐related proteins differing between day and night and/or control versus autism pineal glands. These data show novel and unexpected processes happening in the human pineal gland during the day/night rhythm as well as specific differences between autism donor pineal glands and those from controls.
Published: 2020
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8. Both rare and common genetic variants contribute to autism in the Faroe Islands

Author: Laurence Cuisset, Alexandre Mathieu, Thierry Bienvenu, Jónrit Halling, Coralie Carton, Rannva Biskupstoe, Nathalie Lemière, Thomas Kergrohen, Guðrið Andorsdóttir, Claire S. Leblond, Tormodur Stora, Freddy Cliquet, Jean-François Deleuze, Thomas Bourgeron, Eva Billstedt, Julien Buratti, Guillaume Huguet, Christopher Gillberg, Anne Boland, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), 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), National Hospital of the Faroe Islands [Tórshavn, Faroe Islands], Genetic Biobank of the Faroes [Tórshavn, Faroe Islands], Ministry of Health and The Interior [Faroe Islands], University of the Faroe Islands, University of Gothenburg (GU), Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), University of Glasgow, This work was supported by the Institut Pasteur, Centre National de la Recherche Scientifique, the Assistance Publique—Hôpitaux de Paris, the University Paris Diderot, the Simons Foundation, the Fondation pour la Recherche Médicale [DBI20141231310], the European Commission Horizon 2020 [COSYN], The human brain project, the European Commission Innovative Medicines Initiative [EU-AIMS no. 115300], the Cognacq-Jay foundation, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, and the Agence Nationale de la Recherche (ANR) [SynPathy]. This research was supported by the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013, Bio-Psy and by the INCEPTION program ANR-16-CONV-0005, all managed by the ANR part of the Investment for the Future program., We would like to thank all the participants of the epidemiological and genetic cohorts, the 'progeny' database, Julien Fumey for his R tutorial (https://bioinfo-fr.net/creer-sa-carte-geographique-avec-r), Fabrice de Chaumont for his help with python and Thomas Rolland for his feedback on the revised manuscript., 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-LABX-0013,GENMED,Medical Genomics(2010), ANR-15-NEUR-0007,SynPathy,Key Determinants of Synaptic Excitation-Inhibition Imbalance in Autism Spectrum Disorders - From Genetic Animal Models to Human Patients(2015), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), MATHIEU, Alexandre, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, and Key Determinants of Synaptic Excitation-Inhibition Imbalance in Autism Spectrum Disorders - From Genetic Animal Models to Human Patients - - SynPathy2015 - ANR-15-NEUR-0007 - NEURON II - VALID
Subjects: 0301 basic medicine, CNTNAP2, lcsh:QH426-470, lcsh:Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, behavioral disciplines and activities, Article, 03 medical and health sciences, 0302 clinical medicine, GRIK2, Intellectual disability, mental disorders, Genetics, medicine, Molecular Biology, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, lcsh:R, Genetic variants, Autism spectrum disorders, medicine.disease, Genetic architecture, lcsh:Genetics, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, Autism, 030217 neurology & neurosurgery, SNP array
Abstract: The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions (p = 0.0352) or duplications (p = 0.0352)), higher inbreeding status (p = 0.023) and a higher load of rare homozygous deleterious variants (p = 0.011) compared to controls. Our analysis supports the role of several genes/loci associated with autism (e.g., NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g., GRIK2, ROBO1, NINL, and IMMP2L) or recessive deleterious variants (e.g., KIRREL3 and CNTNAP2) affecting autism-associated genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN, and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism., Genetic correlates of autism in natives of remote islands A study of the genetic architecture of autism among people living on the remote Faroe Islands highlights the role of both common and rare gene variants to autism. Claire Leblond from the Institut Pasteur in Paris, France, and colleagues profiled the genetics of 357 Faroese individuals, including 36 with autism, 136 of their relatives and 185 non-autistic controls. Similar to the findings of genetic studies of autism from elsewhere, the researchers discovered rare structural variants in known autism-associated genes and a few new candidate genes linked to brain function. However, unlike studies from larger mainland populations, they also showed that inbreeding on these remote islands increased the likelihood of carrying two copies of the point mutations that contribute to autism.
Published: 2019
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9. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation

Author: Céline Derbois, Noémie Saut, Philippe Amouyel, Stéphanie Debette, Louisa Goumidi, Elisabetta Castoldi, Manal Ibrahim-Kosta, David M. Smadja, Marine Germain, P. van Doorn, Pierre Morange, Etienne Patin, Marie-Christine Alessi, Pierre Suchon, Robert Olaso, David A. Tregouet, Francis Couturaud, Jean-François Deleuze, Florian Thibord, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie biologique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Sorbonne Université (SU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Recherche en Génomique Humaine (CNRGH), Maastricht University [Maastricht], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, The authors would like to thank three research programs managed by the National Research Agency (ANR) as part of the French Investment for the Future initiative genetic investigations: the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), the French Clinical Research Infrastructure Network on Venous Thrombo-Embolism (F-CRIN INNOVTE) and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05) who partially supported performing genetic investigations in the MARTHA GWAS, MARTHA12, EDITH and FARIVE studies. TF was financially supported by a PhD grant from the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013). vDP was supported by grant nr. 2014-1 from the Dutch Thrombosis Foundation. The present project was supported by a grant from CSL Behring., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0003,F-CRIN,Plateforme Nationale d'Infrastructures de Recherche Clinique(2010), ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), Biochemie, RS: CARIM - R1 - Thrombosis and haemostasis, RS: CARIM - R1.01 - Blood proteins & engineering, RS: Carim - B01 Blood proteins & engineering, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition (C2VN), Université de Brest (UBO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-03-01/10-INBS-0003,F-CRIN,Plateforme Nationale d'Infrastructures de Recherche Clinique(2010), ANR-10-IAHU-0005/10-IAHU-0005,ICAN,ICAN(2010), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: 0301 basic medicine, Male, lcsh:Medicine, Genome-wide association study, polymorphisme, PATHWAY, 0302 clinical medicine, COAGULATION-FACTOR-V, lcsh:Science, Venous Thrombosis, RISK, Multidisciplinary, biology, Factor V, DEFECTS, Venous thrombosis, Female, France, medicine.drug, medicine.medical_specialty, Heterozygote, B-DOMAIN, Médecine humaine et pathologie, Article, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Factor V Leiden, Humans, Allele, GENOME-WIDE ASSOCIATION, coagulation, facteur viii, Alleles, Genetic Association Studies, business.industry, lcsh:R, allèle, medicine.disease, GENE, Minor allele frequency, 030104 developmental biology, Endocrinology, Amino Acid Substitution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, biology.protein, lcsh:Q, Human health and pathology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Activated protein C resistance, business, 030217 neurology & neurosurgery, Protein C, RESISTANCE, thrombose veineuse
Abstract: Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.
Published: 2019
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10. Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease

Author: Ceyzériat, Kelly, Ben Haim, Lucile, Denizot, Audrey, Pommier, Dylan, Matos, Marco, Guillemaud, Océane, Palomares, Marie-Ange, Abjean, Laurene, Petit, Fanny, Gipchtein, Pauline, Gaillard, Marie-Claude, Guillermier, Martine, Bernier, Sueva, Gaudin, Mylène, Auregan, Gwenaëlle, Joséphine, Charlène, Dechamps, Nathalie, Veran, Julien, Langlais, Valentin, Cambon, Karine, Bemelmans, Alexis-Pierre, Baijer, Jan, Bonvento, Gilles, Dhenain, Marc, Deleuze, Jean-François, Oliet, Stéphane, Brouillet, Emmanuel, Hantraye, Philippe, Carrillo-de Sauvage, Maria-Angeles, Olaso, Robert, Panatier, Aude, Escartin, Carole, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), 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)-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 de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Artificial Evolution and Computational Biology (BEAGLE), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurocentre Magendie-U862, Institut François Magendie, and Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Reproductive Biology, Stanford University [Stanford], CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Sanofi-Aventis, Centre for Reserach in Neuroscience, McGill University-Montreal General Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Centre National de Génotypage (CNG), Institut François Magendie, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Inria Grenoble - Rhône-Alpes, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Obstetrics and Gynecology [Stanford], Stanford Medicine, Stanford University-Stanford University, McGill University = Université McGill [Montréal, Canada]-Montreal General Hospital, Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Sud, UMR 967, Fontenay-aux-Roses, France, ANR-16-TERC-0016,DecodAstro,Decoder la complexité de la réactivité astrocytaire dans les maladies neurodégénératives(2016), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-JCJC-1402,ACTIVASTRO,Modulation sélective des astrocytes activés : Suivi in situ par résonance magnétique et contribution à la mort neuronale dans la maladie de Huntington(2010), ANR-11-BSV4-0021,AstroConSyn,Contrôle de la transmission synaptique par la connexine 30 astrogliale: bases moléculaires et impact sur l'activité de réseau pathologique(2011), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, cambon, karine, Decoder la complexité de la réactivité astrocytaire dans les maladies neurodégénératives - - DecodAstro2016 - ANR-16-TERC-0016 - TERC - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Jeunes Chercheuses et Jeunes Chercheurs - Modulation sélective des astrocytes activés : Suivi in situ par résonance magnétique et contribution à la mort neuronale dans la maladie de Huntington - - ACTIVASTRO2010 - ANR-10-JCJC-1402 - JCJC - VALID, and BLANC - Contrôle de la transmission synaptique par la connexine 30 astrogliale: bases moléculaires et impact sur l'activité de réseau pathologique - - AstroConSyn2011 - ANR-11-BSV4-0021 - BLANC - VALID
Subjects: Male, Viral vectors, JAK2-STAT3 pathway, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mice, Transgenic, Mouse models, Hippocampus, lcsh:RC346-429, Amyloid beta-Protein Precursor, Mice, Apolipoproteins E, Neuroinflammation, Alzheimer Disease, Glial Fibrillary Acidic Protein, Presenilin-1, Animals, Aspartic Acid Endopeptidases, Extracellular Signal-Regulated MAP Kinases, Maze Learning, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, Amyloid beta-Peptides, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Excitatory Postsynaptic Potentials, Signaling cascades, Janus Kinase 2, Disease Models, Animal, STAT1 Transcription Factor, Suppressor of Cytokine Signaling 3 Protein, Astrocytes, Mutation, Reactive astrocytes, Amyloid Precursor Protein Secretases, Alzheimer’s disease
Abstract: Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer’s disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies. Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer’s disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits. In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer’s disease. Electronic supplementary material The online version of this article (10.1186/s40478-018-0606-1) contains supplementary material, which is available to authorized users.
Published: 2018
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11. Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus

Author: Lluis Quintana-Murci, Marine Germain, Magnus Fontes, Antoine Toubert, Itauá Leston Araujo, David-Alexandre Trégouët, James P. Di Santo, Emmanuel Clave, Corinne Douay, Silvia Lopez-Lastra, Milena Hasan, Bruno Charbit, Noémie Saut, Breno Luiz Melo-Lima, Darragh Duffy, Cécile Alanio, Jacob Bergstedt, Alejandra Urrutia, Cameron Ross MacPherson, Yan Li, Etienne Patin, Pierre-Emmanuel Morange, Matthew L. Albert, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Alloimmunité-Autoimmunité-Transplantation (A2T), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], Genentech, Inc., Genentech, Inc. [San Francisco], Immunité Innée - Innate Immunity, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), International Group for Data Analysis (IGDA), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, 10-LABX-69-01). I.L.A. was a recipient of the Science without Borders PhD program from Brazil Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). J.B. is a member of the Lund Center for Control of Complex Engineering Systems (LCCC) Linnaeus Center and the Excellence Center at Linköping-Lund in Information Technology (ELLIT) Excellence Center at Lund University and is supported by the ELLIIT Excellence Center. J.P.D.S., Y.L., and S.L.-L. received funding from Institut Pasteur, INSERM, the Laboratoire d’Excellence REVIVE. A.T. and E.C. received funding from ANR grant PriCelAge (ANR-14-CE14-0030-01). Genetic investigations in the MARTHA study were supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), We thank J. Fellay, P. Scepanovic, and C. A. W. Thorball for support with genetic analysis and J.-M. Doisne, G. M. Ranson, and H. Strick-Marchand for support with humanized mouse experiments. We thank V. Asnafi, E. Macintyre, A. Cieslak, and I. André-Schmutz for helpful discussions. We also thank the Centre d’Immunologie Humaine (Institut Pasteur, Paris, France) for support., ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l'âge avancé(2014), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée, Centre recherche en CardioVasculaire et Nutrition (C2VN), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l’âge avancé(2014), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, education.field_of_study, T-cell receptor excision circles, T cell, Population, Genome-wide association study, Locus (genetics), General Medicine, Biology, 3. Good health, Transplantation, 03 medical and health sciences, Haematopoiesis, Thymocyte, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, education
Abstract: International audience; The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.
Published: 2018
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12. MACARON: a python framework to identify and re-annotate multi-base affected codons in whole genome/exome sequence data

Author: Waqasuddin Khan, Tania Cuppens, Thomas Ludwig, David-Alexandre Trégouët, Emmanuelle Génin, Florian Thibord, Jean-François Deleuze, Ganapathi Varma Saripella, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Recherche en Génomique Humaine (CNRGH), FREX Consortium, GENMED Consortium, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Statistics and Probability, Computer science, Computational biology, Biochemistry, Genome, 03 medical and health sciences, 0302 clinical medicine, Data sequences, Humans, Nucleotide, Exome, Codon, Molecular Biology, computer.programming_language, chemistry.chemical_classification, Genome, Human, Computational Biology, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Python (programming language), Computer Science Applications, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, chemistry, Programming Languages, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery, Software
Abstract: Summary Predicted deleteriousness of coding variants is a frequently used criterion to filter out variants detected in next-generation sequencing projects and to select candidates impacting on the risk of human diseases. Most available dedicated tools implement a base-to-base annotation approach that could be biased in presence of several variants in the same genetic codon. We here proposed the MACARON program that, from a standard VCF file, identifies, re-annotates and predicts the amino acid change resulting from multiple single nucleotide variants (SNVs) within the same genetic codon. Applied to the whole exome dataset of 573 individuals, MACARON identifies 114 situations where multiple SNVs within a genetic codon induce an amino acid change that is different from those predicted by standard single SNV annotation tool. Such events are not uncommon and deserve to be studied in sequencing projects with inconclusive findings. Availability and implementation MACARON is written in python with codes available on the GENMED website (www.genmed.fr). Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2018
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13. Contribution to Alzheimer's disease risk of rare variants in TREM_2, SORL_1, and ABCA_7 in 1779 cases and 1273 controls

Author: Céline Bellenguez, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Kilan Le Guennec, Gaël Nicolas, Ganesh Chauhan, David Wallon, Stéphane Rousseau, Anne Claire Richard, Anne Boland, Guillaume Bourque, Hans Markus Munter, Robert Olaso, Vincent Meyer, Adeline Rollin-Sillaire, Florence Pasquier, Luc Letenneur, Richard Redon, Jean-François Dartigues, Christophe Tzourio, Thierry Frebourg, Mark Lathrop, Jean-François Deleuze, Didier Hannequin, Emmanuelle Genin, Philippe Amouyel, Stéphanie Debette, Jean-Charles Lambert, Dominique Campion, Olivier Martinaud, Aline Zarea, Stéphanie Bombois, Marie-Anne Mackowiak, Vincent Deramecourt, Agnès Michon, Isabelle Le Ber, Bruno Dubois, Olivier Godefroy, Frédérique Etcharry-Bouyx, Valérie Chauviré, Ludivine Chamard, Eric Berger, Eloi Magnin, Jean-Francois Dartigues, Sophie Auriacombe, François Tison, Vincent de la Sayette, Dominique Castan, Elsa Dionet, Francois Sellal, Olivier Rouaud, Christel Thauvin, Olivier Moreaud, Mathilde Sauvée, Maïté Formaglio, Hélène Mollion, Isabelle Roullet-Solignac, Alain Vighetto, Bernard Croisile, Mira Didic, Olivier Félician, Lejla Koric, Mathieu Ceccaldi, Audrey Gabelle, Cecilia Marelli, Pierre Labauge, Thérèse Jonveaux, Martine Vercelletto, Claire Boutoleau-Bretonnière, Giovanni Castelnovo, Claire Paquet, Julien Dumurgier, Jacques Hugon, Foucauld De Boisgueheneuc, Serge Belliard, Serge Bakchine, Marie Sarazin, Marie-Odile Barrellon, Bernard Laurent, Frédéric Blanc, Jérémie Pariente, Snejana Jurici, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Excellence Laboratory LabEx DISTALZ, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Metacohorts Consortium, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), McGill University and Genome Quebec Innovation Centre, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie [Lille], Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Institut National de la Santé et de la Recherche Médicale (Inserm)-Université de Bordeaux, Université de Bordeaux (UB), INSERM, Team Psycoépidémiologie du Vieillissement et des Maladies Chroniques - Population Health Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Epidémiologie, santé publique et développement, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR99-ISPED, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Lille, Troubles cognitifs vasculaires et dégénératifs, Université de Lille, Sciences et Technologies, Réseau International des Instituts Pasteur (RIIP), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CNR MAJ collaborators, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 305299,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,AGEDBRAINSYSBIO(2013), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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 Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Male, Adult, Aging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SORL1, Apolipoprotein E4, Genome-wide association study, Biology, ABCA7, 03 medical and health sciences, Young Adult, Immunologic, Alzheimer Disease, Genetic variation, Receptors, medicine, 80 and over, TREM2, Humans, Genetic Predisposition to Disease, Receptors, Immunologic, Genetic Association Studies, LDL-Receptor Related Proteins, Aged, Aged, 80 and over, Genetics, Membrane Glycoproteins, Whole Genome Sequencing, General Neuroscience, Genetic Variation, Membrane Transport Proteins, Heritability, Middle Aged, Alzheimer's disease, medicine.disease, Minor allele frequency, 030104 developmental biology, biology.protein, ATP-Binding Cassette Transporters, Female, Neurology (clinical), Geriatrics and Gerontology, Developmental Biology, Genome-Wide Association Study
Abstract: International audience; We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk~and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10$^{-6}$ was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a~clearer insight into the classes of rare variants involved. Despite different effect sizes and~varying~cumulative minor allele frequencies, the rare protein-truncating and missense-predicted~damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE $\varepsilon$4.
Published: 2017
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14. A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author: Anne-Claude Tabet, Thomas Rolland, Marie Ducloy, Jonathan Lévy, Julien Buratti, Alexandre Mathieu, Damien Haye, Laurence Perrin, Céline Dupont, Sandrine Passemard, Yline Capri, Alain Verloes, Séverine Drunat, Boris Keren, Cyril Mignot, Isabelle Marey, Aurélia Jacquette, Sandra Whalen, Eva Pipiras, Brigitte Benzacken, Sandra Chantot-Bastaraud, Alexandra Afenjar, Delphine Héron, Cédric Le Caignec, Claire Beneteau, Olivier Pichon, Bertrand Isidor, Albert David, Laila El Khattabi, Stephan Kemeny, Laetitia Gouas, Philippe Vago, Anne-Laure Mosca-Boidron, Laurence Faivre, Chantal Missirian, Nicole Philip, Damien Sanlaville, Patrick Edery, Véronique Satre, Charles Coutton, Françoise Devillard, Klaus Dieterich, Marie-Laure Vuillaume, Caroline Rooryck, Didier Lacombe, Lucile Pinson, Vincent Gatinois, Jacques Puechberty, Jean Chiesa, James Lespinasse, Christèle Dubourg, Chloé Quelin, Mélanie Fradin, Hubert Journel, Annick Toutain, Dominique Martin, Abdelamdjid Benmansour, Claire S. Leblond, Roberto Toro, Frédérique Amsellem, Richard Delorme, Thomas Bourgeron, AP-HP Hôpital universitaire Robert-Debré [Paris], 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] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Dijon, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Service de génétique [Hôpial Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire [Grenoble] (CHU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Métropole Savoie [Chambéry], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Hôpital Chubert, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), This work was funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, Centre National de la Recherche Scientifique, University Paris Diderot, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the FondaMental Foundation, the GenMed Labex and the BioPsy Labex. The research leading to these results has received funding from the ERA-Net NEURON Cofund Programme under 'Horizon 2020' (SynPathy project), the ANR SynDivAutism, the Human Brain Project, and 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 Program (FP7/2007-2013) and EFPIA companies’ in kind contribution., We are grateful to the families for participating in this study. We thank Isabelle Cloëz-Tayarani, Ksenia Bagrintseva and Gaël Millot for helpful discussions and careful reading of the manuscript. This study was funded by a French partnership between the Clinical Research Department of the AP-HP Institution and the Institut Pasteur. It was also supported by the PMS French association (Mrs Meunier), 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-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), European Project: 291840,EC:FP7:HEALTH,FP7-ERANET-2011-RTD,ERA-NET NEURON II(2012), European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), 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), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], CHU de Lyon, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier de Chambéry (C.H.de Chambéry), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Herrada, Anthony, 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, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Network of European funding for Neuroscience research - ERA-NET NEURON II - - EC:FP7:HEALTH2012-01-01 - 2015-12-31 - 291840 - VALID, European Autism Interventions - A Multicentre Study for Developing New Medications - EU-AIMS - - EC:FP7:SP1-JTI2012-04-01 - 2017-03-31 - 115300 - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), 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, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: lcsh:Genetics, lcsh:QH426-470, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:R, Neurodevelopmental disorders, lcsh:Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Clinical genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Abstract: International audience; Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes theSHANK3gene.SHANK3is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inheritedSHANK3deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
Published: 2017
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15. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

Author: Aurélie Poulet, Alexandra Benchoua, Richard Delorme, Laure Chatrousse, Francis Cogé, Delphine Héron, Frédérique Rodet-Amsellem, Millan Mark, Claire Boissart, Thomas Bourgeron, Hélène Darville, Anselme L. Perrier, Caroline Nava, Julie Pernelle, Margot Jarrige, Marc Peschanski, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, French Biodiversity Agency, 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, Hydrosystèmes et Bioprocédés (UR HBAN), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Division of General Internal Medicine (DGIM), Université de Genève = University of Geneva (UNIGE), Institut de Recherche Servier, SERVIER, 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), Institut Pasteur [Paris] (IP), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study has been in part funded by grants from 'Investissements d'Avenir' – (ANR-11-INBS-0009 - INGESTEM – and ANR-11-INBS-0011 - NeurATRIS), the French National Research Agency ANR (ANR-13-SAMA-0006, SynDivAutism), the Laboratory of Excellence GENMED (ANR-10-LABX-0013), the Bettencourt-Schueller Foundation, the Cognacq Jay Foundation, and the Fondamental Foundation. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository, as well as clinical data. NINDS Repository sample numbers corresponding to the samples used are GM 1869., The authors are thankful to I-Stem's HTS platform staff for constant technical support. We thank the cell bank of Pitié-Salpétrière hospital and the Clinical Investigation Center of Robert Debré hospital for assistance with patient recruitment, information, sampling and fibroblast preparation. H.D. received a PhD grant from Servier's Laboratories. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon)., ANR-11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), d'Eggis, Gilles, Infrastructures - INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES - - INGESTEM2011 - ANR-11-INBS-0009 - INBS - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Santé Mentale et Addictions - Diversité Synaptique dans l'autisme - - SynDivAutism2013 - ANR-13-SAMA-0006 - SAMENTA - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], University of Geneva [Switzerland], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], ANR-11-INBS-0009/11-INBS-0009,INGESTEM,INFRASTRUCTURE NATIONALE D'INGENIERIE DES CELLULES SOUCHES PLURIPOTENTES(2011), ANR-11-INBS-0011/11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, GAS, Global Assessment Scale, 0301 basic medicine, VPA, valproic acid, Autism Spectrum Disorder, Cellular differentiation, Autism, Human Embryonic Stem Cells, Drug repurposing, MESH: Neurons, lcsh:Medicine, hESC, human embryonic stem cells, Haploinsufficiency, Severity of Illness Index, RPM, Raven's progressive matrices, MESH: Nerve Tissue Proteins, MESH: Neuronal Plasticity, Induced pluripotent stem cell, SHANK3, Cells, Cultured, ASD, autism spectrum disorders, Neurons, ADOS, Autism Diagnosis Observational Scale, Genetics, MESH: Autism Spectrum Disorder, lcsh:R5-920, Neuronal Plasticity, PPVT, Peabody Picture Vocabulary Test, PSC, pluripotent stem cells, Cell Differentiation, General Medicine, Neural stem cell, 3. Good health, Drug repositioning, Phenotype, Autism spectrum disorder, MESH: Pluripotent Stem Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Haploinsufficiency, lcsh:Medicine (General), Research Paper, MESH: Cells, Cultured, Pluripotent Stem Cells, MESH: Cell Differentiation, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Nerve Tissue Proteins, ADHD, Attention Deficit Hyperactive Disorder, Lithium, SHANK3, SH3 and multiple ankyrin repeat domains 3, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, iPSC, induced pluripotent stem cells, 03 medical and health sciences, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, High throughput screening, MESH: Severity of Illness Index, medicine, Humans, NSC, neural stem cells, RNA, Messenger, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], HTS, high throughput screening, MESH: RNA, Messenger, Valproate, MESH: Humans, MESH: Lithium, business.industry, Valproic Acid, MESH: Transcriptome, lcsh:R, MESH: Human Embryonic Stem Cells, medicine.disease, FDA, Food and Drug Administration, Embryonic stem cell, MESH: Male, DMSO, dimethylsulfoxyde, PPIA, Peptidylprolyl Isomerase A, 030104 developmental biology, SRS, Social Responsiveness Scale, Transcriptome, business, Neuroscience, MESH: Valproic Acid
Abstract: Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments., Highlights • Human neurons were used to screen for compounds correcting symptoms associated with SHANK3 haploinsufficiency syndrome. • Screening criteria were the ability to increase SHANK3 expression and to increase glutamatergic transmission. • Selected hit compounds were then validated using neurons differentiated from individuals with SHANK3 disrupting mutations. • Lithium was selected and delivered to one of SHANK3 patient showing encouraging positive clinical outcomes after one year. The clinical heterogeneity between individuals affected by autism makes it difficult to anticipate the effectiveness of a treatment. Furthermore, clinical practice lacks biological tools to help make such decisions. Here we use neurons, produced from pluripotent stem cells derived from patients affected by SHANK3 haploinsufficiency syndrome, to test the efficiency of therapeutic compounds. We screened the biological activity of more than 200 compounds on SHANK3 expression. Lithium was ultimately selected and delivered to one patient with a SHANK3-disruptive mutation. This resulted in a positive outcome, as determined by improved autistic core symptoms, thus supporting the usefulness of this type of predictive approach.
Published: 2016
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16. Nicotine consumption is regulated by a human polymorphism in dopamine neurons

Author: Walter Fratta, Philippe Faure, M. De Biasi, Y. A. H. Hay, Stéphanie Pons, Fabio Marti, Liana Fattore, Carole Morel, Mark Lathrop, Bertrand Lambolez, Uwe Maskos, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), 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), Réseau cortical et couplage neurovasculaire = Cortical Network and Neurovascular (NPS-03), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur, Centre National de la Recherche Scientifique CNRS [UMR 3571, UMR 7102], ATIP programme, FP7 ERANET Neuron NICO-GENE network, LabEx GENMED - ANR, NIH [DA029157, U19CA148127], Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Italy, Agence Nationale pour la Recherche, la Fondation pour la Recherche Medicale (FRM equipe PF), fondation pour la the Neuropole de Recherche Francilien (NeRF) of Ile de France, Bettencourt Schueller Foundation, National Cancer Institute INCa BIO-SILC programme, Ecole des Neurosciences de Paris (ENP), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), European Project: 680966,ERA-NET NEURON,NICO-GENE(2015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Neurosciences Paris Seine (NPS)
Subjects: Male, Nicotine, Action Potentials, Self Administration, lentiviral vectors, Biology, Pharmacology, Receptors, Nicotinic, Polymorphism, Single Nucleotide, Article, human polymorphisms, smoking, Cellular and Molecular Neuroscience, Mice, In vivo, Dopamine, medicine, Animals, mouse models, Receptor, Molecular Biology, Mice, Knockout, dopamine system, in vivo electrophysiology, Dopaminergic Neurons, Dopaminergic, Ventral Tegmental Area, nicotine self-administration, 3. Good health, Ventral tegmental area, Psychiatry and Mental health, Nicotinic acetylcholine receptor, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cell activation, nicotinic receptor, Neuroscience, Reinforcement, Psychology, medicine.drug
Abstract: International audience; Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor nAChR) a3, a5 and beta 4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the a5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive a5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant a5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for a5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous a5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.
Published: 2014
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16 results on '"ANR-10-LABX-0013,GENMED,Medical Genomics(2010)"'

1. Association of ABO blood groups with venous thrombosis recurrence in middle-aged patients: insights from a weighted Cox analysis dedicated to ambispective design

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

3. Common and Rare 5'UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics

4. An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

5. Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition

6. Decreased phenol sulfotransferase activities associated with hyperserotonemia in autism spectrum disorders

7. Mass‐spectrometry analysis of the human pineal proteome during night and day and in autism

8. Both rare and common genetic variants contribute to autism in the Faroe Islands

9. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation

10. Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease

11. Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus

12. MACARON: a python framework to identify and re-annotate multi-base affected codons in whole genome/exome sequence data

13. Contribution to Alzheimer's disease risk of rare variants in TREM_2, SORL_1, and ABCA_7 in 1779 cases and 1273 controls

14. A framework to identify contributing genes in patients with Phelan-McDermid syndrome

15. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

16. Nicotine consumption is regulated by a human polymorphism in dopamine neurons

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16 results on '"ANR-10-LABX-0013,GENMED,Medical Genomics(2010)"'

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