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

Author: Aline Vitrac, Claire S. Leblond, Thomas Rolland, Freddy Cliquet, Alexandre Mathieu, Anna Maruani, Richard Delorme, Michael Schön, Andreas M. Grabrucker, Conny van Ravenswaaij-Arts, Katy Phelan, Anne-Claude Tabet, Thomas Bourgeron, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universität Ulm - Ulm University [Ulm, Allemagne], University of Limerick (UL), University of Groningen [Groningen], Florida Hospital Cancer Institute, This study has been supported by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA). ERN-ITHACA is partly co-funded by the Health Programme of the European Union. Funding was also obtained from the European Union's Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N° 825575. This work was also funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris Cité, the Eranet-Neuron (ALTRUISM), the Association Française du Syndrome Phelan-mcDermid and the Association Téhani et les enfants Phelan-McDermid, the GenMed Labex, AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement N° 777394 and the INCEPTION program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the European Union's Horizon 2020 research and innovative program CANDY under grant agreement N° 847818., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 825575,COFUND-EJP, European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Epilepsy, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, Neurodevelopmental disorders, Genetics, Phelan-McDermid syndrome, General Medicine, Brain development, SHANK3, Genetics (clinical)
Abstract: International audience; SHANK3-related Phelan-McDermid syndrome (PMS) is caused by a loss of the distal part of chromosome 22, including SHANK3, or by a pathological SHANK3 variant. There is an important genetic and phenotypic diversity among patients who can present with developmental delay, language impairments, autism, epilepsy, and other symptoms. SHANK3, encoding a synaptic scaffolding protein, is deleted in the majority of patients with PMS and is considered a major gene involved in the neurological impairments of the patients. However, differences in deletion size can influence clinical features, and in some rare cases, deletions at the 22q13 locus in individuals with SHANK3-unrelated PMS do not encompass SHANK3. These individuals with SHANK3-unrelated PMS still display a PMS-like phenotype. This suggests the participation of other 22q13 genes in the pathogenesis of PMS. Here, we review the biological function and potential implication in PMS symptoms of 110 genes located in the 22q13 region, focusing on 35 genes with evidence for association with neurodevelopmental disorders, including 13 genes for epilepsy and 11 genes for microcephaly and/or macrocephaly. Our review is restricted to the 22q13 region, but future large-scale studies using whole genome sequencing and deep-phenotyping are warranted to develop predictive models of clinical trajectories and to target specific medical and educational care for each individual with PMS.
Published: 2023
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2. 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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3. Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

Author: Odelin, Gaelle, Faucherre, Adèle, Marchese, Damien, Pinard, Amélie, Jaouadi, Hager, Le Scouarnec, Solena, Deleuze, Jean-François, Génin, Emmanuelle, Lindenbaum, Pierre, Redon, Richard, Schott, Jean-Jacques, Chiarelli, Raphaël, Achouri, Younes, Faure, Emilie, Herbane, Marine, Théron, Alexis, Avierinos, Jean-François, Jopling, Chris, Collod-Béroud, Gwenaëlle, Rezsohazy, René, Zaffran, Stéphane, UCL - SST/LIBST - Louvain Institute of Biomolecular Science and Technology, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut du Thorax [Nantes], Département de Cardiologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), 'Association Française contre les Myopathies' [NMH-Decrypt Project],the 'Fondation pour la Recherche Médicale'[DPC20111123002], the 'Institut National de la Santé et de laRecherche Médicale' and 'la Fondation Leducq' to S.Z. This workwas supported by the 'Fonds de la recherche Scientifique FNRS'[Crédit de recherche (CDR) J.0157.21] and the 'Fonds spéciaux derecherche' (FSR, UCLouvain) to R.R. A.P. received PhD fellowshipsfrom the 'Association Française du syndrome de Marfan et apparentés'.A.F. and C.J. are members of the Laboratory of ExcellenceIon Channel Science and Therapeutics supported by a grant fromthe ANR. Work in the C.J lab is supported by a grant from the 'laFondation Leducq', ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), and ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Organogenesis, General Biochemistry, General Physics and Astronomy, Genetics and Molecular Biology, General Chemistry, Development, Heart development, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1 −1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1 −/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.
Published: 2023
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4. 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

5. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

Author: Estelle Colin, Yannis Duffourd, Emilie Tisserant, Raissa Relator, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Hana Safraou, Julian Delanne, Nolwenn Jean-Marçais, Boris Keren, Bertrand Isidor, Marie Vincent, Cyril Mignot, Delphine Heron, Alexandra Afenjar, Solveig Heide, Anne Faudet, Perrine Charles, Sylvie Odent, Yvan Herenger, Arthur Sorlin, Sébastien Moutton, Jennifer Kerkhof, Haley McConkey, Martin Chevarin, Charlotte Poë, Victor Couturier, Valentin Bourgeois, Patrick Callier, Anne Boland, Robert Olaso, Christophe Philippe, Bekim Sadikovic, Christel Thauvin-Robinet, Laurence Faivre, Jean-François Deleuze, Antonio Vitobello, Jonchère, Laurent, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), London Health Sciences Center (LHSC), CHU Dijon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Sorbonne Université (SU), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Western Ontario (UWO), The study was performed within the framework of the GAD (Génétique des Anomalies du Développement) collection and approved by the appropriate institutional review board of Dijon University Hospital (DC2011-1332). This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs (PERSONALISE), and the Burgundy-Franche-Compté regional council (INTEGRA). The sequencing platform at the CNRGH was supported by the France Génomique National infrastructure, funded as part of the 'Investissements d’Avenir' program, managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09). The whole genome sequencing performed at the CNRGH was funded by the Laboratory of Excellence GENMED (Medical Genomics) Grant No. ANR-10-LABX-0013, managed by the National Research Agency (ANR) as part of the Investment for the Future program., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and ANR-10-LABX-0013,GENMED,Medical Genomics(2010)
Subjects: genome sequencing, DNA methylation analysis, [SDV.GEN]Life Sciences [q-bio]/Genetics, translational research, Cell Biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, transcriptome sequencing, undiagnosed neurodevelopmental diseases, Developmental Biology
Abstract: Purpose: Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases.Methods: We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis.Results: The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood.Conclusion: Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.
Published: 2022
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6. 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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7. 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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8. Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

Author: Jean-François Deleuze, Thomas Ludwig, Emmanuelle Génin, Hervé Perdry, Ozvan Bocher, Pierre-Emmanuel Morange, Suryakant Suryakant, David-Alexandre Trégouët, Gaëlle Marenne, Jacob Odeberg, Admin, Oskar, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, 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), Helmholtz Zentrum München = German Research Center for Environmental Health, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre National de Recherche en Génomique Humaine (CNRGH), 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), 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), Royal Institute of Technology [Stockholm] (KTH ), University of Tromsø (UiT), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), 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), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Agence Nationale de la Recherche, and ANR-10-LABX-0013,GENMED,Medical Genomics(2010)
Subjects: Cancer Research, Computer science, Association (object-oriented programming), Genetic Variation, High-Throughput Nucleotide Sequencing, Computational biology, Genomics, computer.software_genre, Genome, Annotation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics, Computer Aided Design, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, DNA, Intergenic, Exome, computer, Venous thromboembolism, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Coding (social sciences), Sequence (medicine)
Abstract: Rare variant association tests (RVAT) have been developed to study the contribution of rare variants widely accessible through high-throughput sequencing technologies. RVAT require to aggregate rare variants in testing units and to filter variants to retain only the most likely causal ones. In the exome, genes are natural testing units and variants are usually filtered based on their functional consequences. However, when dealing with whole-genome sequence (WGS) data, both steps are challenging. No natural biological unit is available for aggregating rare variants. Sliding windows procedures have been proposed to circumvent this difficulty, however they are blind to biological information and result in a large number of tests.We propose a new strategy to perform RVAT on WGS data: “RAVA-FIRST” (RAre Variant Association using Functionally-InfoRmed STeps) comprising three steps. (1) New testing units are defined genome-wide based on functionally-adjusted Combined Annotation Dependent Depletion (CADD) scores of variants observed in the GnomAD populations, which are referred to as “CADD regions”. (2) A region-dependent filtering of rare variants is applied in each CADD region. (3) A functionally-informed burden test is performed with sub-scores computed for each genomic category within each CADD region. Both on simulations and real data, RAVA-FIRST was found to outperform other WGS-based RVAT. Applied to a WGS dataset of venous thromboembolism patients, we identified an intergenic region on chromosome 18 that is enriched for rare variants in early-onset patients and that was that was missed by standard sliding windows procedures.RAVA-FIRST enables new investigations of rare non-coding variants in complex diseases, facilitated by its implementation in the R package Ravages.Author SummaryTechnological progresses have made possible whole genome sequencing at an unprecedented scale, opening up the possibility to explore the role of genetic variants of low frequency in common diseases. The challenge is now methodological and requires the development of novel methods and strategies to analyse sequencing data that are not limited to assessing the role of coding variants. With RAVA-FIRST, we propose a novel strategy to investigate the role of rare variants in the whole-genome that takes benefit from biological information. Especially, RAVA-FIRST relies on testing units that go beyond genes to gather rare variants in the association tests. In this work, we show that this new strategy presents several advantages compared to existing methods. RAVA-FIRST offers an easy and straightforward analysis of genome-wide rare variants, especially the intergenic ones which are frequently left behind, making it a promising tool to get a better understanding of the biology of complex diseases.
Published: 2022
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9. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Author: Magdalena Harakalova, Benjamin Meder, Philippe Charron, Manuel Gómez-Bueno, Jorg J. A. Calis, François Cambien, David-Alexandre Trégouët, Maurizia Grasso, Steven McGinn, Uwe Völker, Thomas Meitinger, Stefan Weiss, L. Duboscq-Bidot, Richard Dorent, Vera Regitz-Zagrosek, Folkert W. Asselbergs, Hélène Blanché, Olivier Dubourg, Patrick Lacolley, Pierre Boutouyrie, Delphine Bacq-Daian, Vincent Fontaine, Volker Ruppert, Marine Germain, K Lehnert, Jean-Noël Trochu, Stuart A. Cook, Angélique Curjol, Brendan J. Keating, Ibticem Raji, Anne Boland, J. Erdmann, Michael Morley, Jean-François Aupetit, Paloma Remior, Luigi Tavazzi, Gérard Roizès, Michal Mokry, Konstantin Strauch, Richard Isnard, Jean-Philippe Empana, Robert Olaso, Kenneth B. Marguiles, Zofia T. Bilińska, Stephan B. Felix, Marcus Dörr, Thomas P. Cappola, Stefan Blankenberg, Jan Haas, Céline Besse, Jean-François Deleuze, Christine E. Seidman, Christian Hengstenberg, Jessica van Setten, Hakon Hakonarson, Sanjay K Prasad, Daiane Hemerich, Pascal de Groote, Thomas Wichter, Alain van Mil, Michel Komajda, Renee Maas, Carole Proust, Declan P. O'Regan, Xavier Jouven, Ganapathi Varma Saripella, Georgios Kararigas, Eloisa Arbustini, Jin Li, Klaus Stark, Laurent Fauchier, Flavie Ader, Melanie Waldenberger, Martina Müller-Nurasyid, Eric Villard, Sophie Garnier, Cardiology, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, 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) (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), Service de Cardiologie [CHU Pitié-Salpêtrière], 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 Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique-Hôpitaux de Paris, Fondation Leducq, Société Française de Cardiologie, Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München, Université de Bordeaux, Medical Research Council, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), 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), 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), University Medical Center [Utrecht], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pennsylvania, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), National Heart Centre Singapore (NHCS), Children’s Hospital of Philadelphia (CHOP ), University of Regensburg, Royal Brompton Hospital, Imperial College London, Istituti Clinici Scientifici Maugeri [Pavia] (IRCCS Pavia - ICS Maugeri), Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Medical Center of the Johannes Gutenberg-University Mainz, Perelman School of Medicine, Harvard Medical School [Boston] (HMS), University of Iceland [Reykjavik], Heidelberg University, Stanford University Medical School, 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), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universität zu Lübeck = University of Lübeck [Lübeck], Universitätklinikum Gießen und Marburg GmbH, Maria Cecilia Hospital [Cotignola], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), Centre hospitalier Saint Joseph - Saint Luc [Lyon], National Institute of Cardiology [Varsovie, Pologne], University of Medicine Greifswald, Centre de Référence Maladies Cardiaques Héréditaires, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Swedish University of Agricultural Sciences (SLU), 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), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Groupe Hospitalier Paris Saint Joseph, Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), and University College of London [London] (UCL)
Subjects: Cardiac & Cardiovascular Systems, Cardiomyopathy, Dilated/genetics, [SDV]Life Sciences [q-bio], Signal Transducing/genetics, Dilated cardiomyopathy, Genome-wide association study, Adaptor Proteins, Signal Transducing/genetics, 030204 cardiovascular system & hematology, TAURINE, 0302 clinical medicine, GWAS, Medicine, POSITION STATEMENT, 1102 Cardiorespiratory Medicine and Haematology, Genetics, 0303 health sciences, education.field_of_study, Genetic Predisposition to Disease/genetics, Adaptor Proteins, 4C-sequencing, Polymorphism, Single Nucleotide/genetics, Genetic risk score, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Single Nucleotide/genetics, Cardiomyopathy, Dilated, Cardiomyopathy, Population, Locus (genetics), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Chromosomes, 03 medical and health sciences, Systolic/genetics, Heart Failure, Systolic/genetics, SNP, Animals, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, Imputation, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Heart Failure, Science & Technology, business.industry, WORKING GROUP, 1103 Clinical Sciences, medicine.disease, Genetic architecture, Cardiovascular System & Hematology, Dilated/genetics, Cardiovascular System & Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Apoptosis Regulatory Proteins, Heart Failure, Systolic, Genome-Wide Association Study
Abstract: Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
Published: 2021
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10. The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

Author: Elena Gargaun, Sestina Falcone, Guilhem Solé, Julien Durigneux, Andoni Urtizberea, Jean Marie Cuisset, Sofia Benkhelifa-Ziyyat, Laura Julien, Anne Boland, Florian Sandron, Vincent Meyer, Jean François Deleuze, David Salgado, Jean-Pierre Desvignes, Christophe Béroud, Anatole Chessel, Alexia Blesius, Martin Krahn, Nicolas Levy, France Leturcq, France Pietri-Rouxel, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Reference des Maladies Neuromusculaires - Atlantique Occitanie Caraïbe (CRMN - AOC), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, HAL Sorbonne Université 5, Centre de recherche en myologie, Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU de Bordeaux Pellegrin [Bordeaux], Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France [Paris], Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Université Paris-Saclay, Aix Marseille Université (AMU), Hôpital Cochin [AP-HP], Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Centre de Recherche en Myologie, ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Centre de Reference des Maladies Neuromusculaires AOC, Partenaires INRAE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X)
Subjects: musculoskeletal diseases, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, lncRNA, medicine, long noncoding RNA, Muscular dystrophy, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Myogenesis, medicine.disease, Non-coding RNA, ncRNA, Long non-coding RNA, Exon skipping, lcsh:Biology (General), Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), Cancer research, biology.protein, Biomarker (medicine), Protein stabilization, Dystrophin, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.
Published: 2021
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11. 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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12. 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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13. 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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14. Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Author: Christian Kubisch, Robert Rubinsztajn, Arianne Llamos Paneque, Philippe Manivet, Catarina Pereira, Laila Selim, Nathalie Escande-Beillard, Abigail Loh, Peter Bauer, Catherine Bartoli, Song-Hua Lee, Morgane Le Mao, Hϋlya Kayserili, Coraline Airault, Nihal M. Al Menabawy, Lisa Martino, Yosef Gruenbaum, Guy Lenaers, Antoine Muchir, Agnès Rötig, Annachiara De Sandre-Giovannoli, Nicolas Lévy, Sahar Elouej, Sheela Nampoothiri, Chayki Charar, Jean-François Deleuze, Karim Harhouri, Bruno Reversade, Davor Lessel, Geneviève Baujat, ACS - Heart failure & arrhythmias, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Amrita Institute of Medical Sciences and Research Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Koç University, Cairo University Children Hospital, Medical Genetics Service Specialties Hospital, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hôpital Necker, The Hebrew University of Jerusalem (HUJ), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CENTOGENE AG, Institute of Medical Biology A*STAR, Sorbonne Université (SU), CeleScreen SAS, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), 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), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), 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)-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), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), LENAERS, Guy, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Escande-Beillard, Nathalie, Reversade, Bruno, Elouej,Sahar, Harhouri, Karim, Le Mao, Morgane, Baujat, Genevieve, Nampoothiri, Sheela, Menabawy, Nihal Al, Selim, Laila, Paneque, Arianne Llamos, Kubisch, Christian, Lessel, Davor, Rubinsztajn,Robert, Charar, Chayki, Bartoli, Catherine, Airault, Coraline, Deleuze, Jean-François, Rötig, Agnes, Bauer, Peter, Pereira, Catarina, Loh, Abigail, Muchir, Antoine, Martino, Lisa, Gruenbaum, Yosef, Lee, Song-Hua, Manivet, Philippe, Lenaers, Guy, Lévy, Nicolas, De Sandre-Giovannoli, Annachiara, and School of Medicine
Subjects: 0301 basic medicine, Premature aging, Senescence, Pathology, medicine.medical_specialty, endocrine system, animal structures, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Apoptosis, General Biochemistry, Genetics and Molecular Biology, Progeroid syndromes, Article, Nuclear envelope, LMNA, 03 medical and health sciences, 0302 clinical medicine, Mitophagy, Genetics research, medicine, lcsh:Science, Multidisciplinary, business.industry, Glomerulosclerosis, General Chemistry, Energy metabolism, medicine.disease, 3. Good health, Mandibuloacral dysplasia, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mitochondrial Membrane Protein, Next-generation sequencing, Medicine, lcsh:Q, business, 030217 neurology & neurosurgery
Abstract: Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features., Association Française contre les Myopathies (AFM); Deutsche Forschungsgemeinschaft; GENMED Laboratory of Excellence on Medical Genomics, Agence Nationale de la Recherche; Institut National de la Santé et de la Recherche Médicale (INSERM); Aix-Marseille University (AMU) by the RAREMED Amidex Project
Published: 2020
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15. A novel rare c.-39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codone

Author: Labrouche-Colomer, Sylvie, Soukarieh, Omar, Proust, Carole, Mouton, Christine, Huguenin, Yoann, Roux, Maguelonne, Besse, Céline, Boland, Anne, Olaso, Robert, Constans, Joël, Deleuze, Jean-François, Morange, Pierre-Emmanuel, Jaspard-Vinassa, Béatrice, Trégouët, David-Alexandre, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'hématologie, 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 Bordeaux [Bordeaux], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine, Institut de Génomique, CEA, Evry, France, 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), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), 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), This work was supported by the GENMED Laboratory of Excellence on Medical Genomics [grant number ANR-10-LABX-0013 (to O.S. and M.R.)], the «EPIDEMIOM-VTE» Senior Chair from the Initiative of Excellence of the University of Bordeaux [grant number ANR No.–10–IDEX-03-02 (to D.A.T.)], partially supported by the French Clinical Research Infrastructure Network on Venous Thrombo-Embolism (F-CRIN INNOVTE), and two research programs managed by the National Research Agency (ANR) as part of the French Investment for the Future., ANR-10-IDEX-0003,IDEX BORDEAUX,Initiative d'excellence de l'Université de Bordeaux(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université de Paris (UP), Boullé, Christelle, Initiative d'excellence de l'Université de Bordeaux - - IDEX BORDEAUX2010 - ANR-10-IDEX-0003 - IDEX - VALID, and Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID
Subjects: Male, Base Sequence, Codon, Initiator, Pedigree, Protein S, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, open reading frame, Protein S deficiency, Young Adult, genomic medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, VINTAGE, Protein Biosynthesis, Humans, Female, Venos Thrombosis, mutation, 5' Untranslated Regions, HeLa Cells
Abstract: International audience; Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG→ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This work describes the first example of 5'UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics.
Published: 2020
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16. 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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17. Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume

Author: Anna Maruani, Guillaume Dumas, Anita Beggiato, Nicolas Traut, Hugo Peyre, Alicia Cohen-Freoua, Frédérique Amsellem, Monique Elmaleh, David Germanaud, Jean-Marie Launay, Thomas Bourgeron, Roberto Toro, Richard Delorme, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche en NeuroImagerie Applicative Clinique et Translationnelle (UNIACT), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-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, Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Institut Pasteur, CNRS, INSERM, AP-HP, University Paris Diderot, the Cognacq-Jay foundation, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, the ANR (SynDivAutism), and the Labex GenMed and BioPsy., ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and ANR-11-IDEX-0004-02/11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011)
Subjects: circadian rhythm, medicine.medical_specialty, endocrine system, Control participant, pineal gland, lcsh:RC435-571, autism spectrum disorder, Melatonin, 03 medical and health sciences, Pineal gland, 0302 clinical medicine, children, Internal medicine, lcsh:Psychiatry, medicine, In patient, Circadian rhythm, sleep, Original Research, Morning, Psychiatry, business.industry, medicine.disease, Volumetric measurement, 030227 psychiatry, Psychiatry and Mental health, medicine.anatomical_structure, Endocrinology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, medicine.drug, MRI
Abstract: International audience; While low plasma melatonin, a neuro-hormone synthesized in the pineal gland, has been frequently associated with autism, our understanding of the mechanisms behind it have remained unclear. In this exploratory study, we hypothesized that low melatonin levels in ASD could be linked to a decrease of the pineal gland volume (PGV). PGV estimates with magnetic resonance imaging (MRI) with a voxel-based volumetric measurement method and early morning plasma melatonin levels were evaluated for 215 participants, including 78 individuals with ASD, 90 unaffected relatives, and 47 controls. We first found that both early morning melatonin level and PGV were lower in patients compared to controls. We secondly built a linear model and observed that plasma melatonin was correlated to the group of the participant, but also to the PGV. To further understand the relationship between PGV and melatonin, we generated a normative model of the PGV relationship with melatonin level based on control participant data. We found an effect of PGV on normalized melatonin levels in ASD. Melatonin deficit appeared however more related to the group of the subject. Thus, melatonin variations in ASD could be mainly driven by melatonin pathway dysregulation.
Published: 2019
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18. 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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19. 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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20. 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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21. Experimenting with reproducibility: a case study of robustness in bioinformatics

Author: Jean-Baptiste Poline, Guillaume Dumas, Yang-Min Kim, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), McGill University = Université McGill [Montréal, Canada], This work was supported by the following: Institut Pasteur (http://dx.doi.org/10.13039/501100003762), H2020 Societal Challenges (http://dx.doi.org/10.13039/100010676), Centre National de la Recherche Scientifique (http://dx.doi.org/10.13039/501100004794), Université Paris Diderot (http://dx.doi.org/10.13039/501100005736), Conny-Maeva Charitable Foundation, Cognacq-Jay Foundation, Orange (http://dx.doi.org/10.13039/501100003951), Fondation pour la Recherche Médicale (http://dx.doi.org/10.13039/501100002915), GenMed Labex, and BioPsy Labex. J.-B.P. was partially funded by NIH-NIBIB P41 EB019936 (ReproNim) NIH-NIMH R01 MH083320 (CANDIShare) and NIH 5U24 DA039832 (NIF), as well as the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative, We thank Thomas Rolland and Freddy Cliquet for sharing their technical advice and comments. Y-M.K. and G.D. thank Thomas Bourgeron for his continuous support on this project, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), McGill University, ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and ANR-11-IDEX-0004-02/11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011)
Subjects: 0301 basic medicine, Computer science, Health Informatics, Review, robustness, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Documentation, Software, Robustness (computer science), Neoplasms, Computer cluster, Humans, cancer, MATLAB, reproducibility, License, computer.programming_language, Reusability, standard consensus dataset, business.industry, network based stratification, Computational Biology, Reproducibility of Results, Python (programming language), Computer Science Applications, 030104 developmental biology, Data Interpretation, Statistical, reusability, Programming Languages, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer, Algorithms, 030217 neurology & neurosurgery
Abstract: International audience; Reproducibility has been shown to be limited in many scientific fields. This question is a fundamental tenet of scientific activity, but the related issues of reusability of scientific data are poorly documented. Here, we present a case study of our difficulties in reproducing a published bioinformatics method even though code and data were available. First, we tried to re-run the analysis with the code and data provided by the authors. Second, we reimplemented the whole method in a Python package to avoid dependency on a MATLAB license and ease the execution of the code on a high-performance computing cluster. Third, we assessed reusability of our reimplementation and the quality of our documentation, testing how easy it would be to start from our implementation to reproduce the results. In a second section, we propose solutions from this case study and other observations to improve reproducibility and research efficiency at the individual and collective levels.While finalizing our code, we created case-specific documentation and tutorials for the associated Python package StratiPy. Readers are invited to experiment with our reproducibility case study by generating the two confusion matrices (see more in section "Robustness: from MATLAB to Python, language and organization"). Here, we propose two options: a step-by-step process to follow in a Jupyter/IPython notebook or a Docker container ready to be built and run.
Published: 2018
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22. 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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23. Genome-Wide Association Study Identifies a Novel Genetic Risk Factor for Recurrent Venous Thrombosis

Author: Hugoline G. de Haan, Astrid van Hylckama Vlieg, David-Alexandre Trégouët, Jean-François Deleuze, Frits R. Rosendaal, Marine Germain, Trevor Baglin, Universiteit Leiden, 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), Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Netherlands Heart Foundation [NHS98.113, NHS208B086, 89.063], Dutch Cancer Foundation [RUL 99/1992], Netherlands Organization for Scientific Research [912-03-033vertical bar2003, 916.56.157], follow-up study by grant Prevention Fund/ZonMW [2827170], ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Universiteit Leiden [Leiden], 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) (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, Recurrent venous thrombosis, genome-wide association study, business.industry, [SDV]Life Sciences [q-bio], Genome-wide association study, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, Bioinformatics, Thrombophilia, Recurrence risk, 03 medical and health sciences, Venous thrombosis, 030104 developmental biology, 0302 clinical medicine, factor V Leiden, Factor V Leiden, medicine, risk factors, venous thrombosis, Genetic risk, Genetic risk factor, business, thrombophilia
Abstract: Background: Genetic risk factors for a first venous thrombosis (VT) seem to have little effect on recurrence risk. Therefore, we aimed specifically to identify novel genetic determinants of recurrent VT. To date, genome-wide association studies are lacking. Methods and Results: We performed a genome-wide association scan in 1279 patients from the MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) follow-up study; 832 patients who remained recurrence free during a median follow-up time of 6.1 years and 447 recurrent VT patients with a median time-to-recurrence of 2.6 years. We analyzed genotype probabilities of ≈8.6 million variants, imputed to the Genome of the Netherlands project reference panel, with a minor allele frequency ≥1% for an association with recurrent VT. One region exceeded genome-wide significance ( P ≤5×10 − 8 ), mapping to the well-known factor V Leiden locus. Conditional association analyses on factor V Leiden did not yield any secondary association signals. We also identified 52 suggestive association signals ( P −5 ) at 17 additional loci. None of these loci were previously implicated in VT risk. Replication analyses for 17 lead variants were performed in 350 patients with recurrent VT and 1866 patients with a single VT event from the MEGA follow-up study, THE-VTE (Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism) study, and LETS (Leiden Thrombophilia Study). We observed an association with recurrence for an intergenic variant at 18q22.1 with an odds ratio of 1.7 (95% confidence interval, 1.2–2.6) per copy of the minor allele. Conclusions: We confirmed the association of factor V Leiden and identified a novel risk locus at 18q22.1 in the first large genetic study on recurrent VT.
Published: 2018
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24. 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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25. 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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26. Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus

Author: Odile Boespflug-Tanguy, Jean-Pierre Desvignes, Ana Borges-Correia, Imen Dorboz, Marc Delepine, Nadine Girard, Laurent Villard, Pierre Sarda, Jean-Christophe Roux, Catherine Badens, Pierre Cacciagli, Pierre Cau, Julie Sutera-Sardo, Mark Lathrop, Nicolas Lévy, Génétique Médicale et Génomique Fonctionnelle (GMGF), 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)-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Villard, Laurent, and Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID
Subjects: Male, Programmed cell death, Golgi Apparatus, Deafness, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Young Adult, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Report, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetics(clinical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, Cell Shape, Myelin Sheath, Genetics (clinical), 030304 developmental biology, Dystonia, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Endoplasmic reticulum, Infant, Membrane Proteins, Genetic Diseases, X-Linked, Fibroblasts, Golgi apparatus, 16. Peace & justice, medicine.disease, Phenotype, Pedigree, Crosstalk (biology), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Membrane protein, Child, Preschool, Mutation, Unfolded protein response, symbols, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: International audience; BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways , including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.
Published: 2013
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27. 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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28. Current knowledge on the genetics of autism and propositions for future research

Author: Thomas Bourgeron, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This work was funded by the Institut Pasteur, the Bettencourt-Schueller foundation, the 'Centre national de la recherche scientifique', Paris Diderot University, the 'Agence nationale de la recherche' (SynDiv-ASD), the GenMed labex, the BioPsy labex, the Conny-Maeva Charitable Foundation, the Cognacq-Jay Foundation, the Orange Foundation, and the Fondamental Foundation., I thank Guillaume Huguet for drawing the figures., ANR-10-LABX-0013,GENMED,Medical Genomics(2010), ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition, ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), and ANR-11-IDEX-0004-02/11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011)
Subjects: 0301 basic medicine, Candidate gene, genetic structures, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Gene Dosage, Troubles du spectre autistique, MESH: Gene Dosage, Autism Spectrum disorders, [SCCO]Cognitive science, 0302 clinical medicine, Intellectual disability, Heritability of autism, Exome, Medicine(all), MESH: Autism Spectrum Disorder, Genetics, Agricultural and Biological Sciences(all), MESH: Polymorphism, Single Nucleotide, General Medicine, Synapse, Twin Studies as Topic, 3. Good health, Autism spectrum disorder, Études de jumeaux, General Agricultural and Biological Sciences, Psychology, Clinical psychology, MESH: Mutation, CNV, MESH: Autistic Disorder, behavioral disciplines and activities, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Twin studies, Heritability, 03 medical and health sciences, Immunology and Microbiology(all), SNV, mental disorders, medicine, Humans, Autistic Disorder, MESH: Humans, General Immunology and Microbiology, Biochemistry, Genetics and Molecular Biology(all), Héritabilité, medicine.disease, Twin study, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Mutation, MESH: Twin Studies as Topic, Autism, 030217 neurology & neurosurgery
Abstract: International audience; Autism spectrum disorders (ASD) are a heterogeneous group of neuropsychiatric disorders characterized by problems in social communication, as well as by the presence of restricted interests, stereotyped and repetitive behaviours. In the last 40years, genetic studies have provided crucial information on the causes of ASD and its diversity. In this article, I will first review the current knowledge on the genetics of ASD and then suggest three propositions to foster research in this field. Twin and familial studies estimated the heritability of ASD to be 50%. While most of the inherited part of ASD is captured by common variants, our current knowledge on the genetics of ASD comes almost exclusively from the identification of highly penetrant de novo mutations through candidate gene or whole exome/genome sequencing studies. Approximately 10% of patients with ASD, especially those with intellectual disability, are carriers of de novo copy-number (CNV) or single nucleotide variants (SNV) affecting clinically relevant genes for ASD. Given the function of these genes, it was hypothesized that abnormal synaptic plasticity and failure of neuronal/synaptic homeostasis could increase the risk of ASD. In addition to these discoveries, three propositions coming from institutions, researchers and/or communities of patients and families can be made to foster research on ASD: (i) to use more dimensional and quantitative data than diagnostic categories; (ii) to increase data sharing and research on genetic and brain diversity in human populations; (iii) to involve patients and relatives as participants for research. Hopefully, this knowledge will lead to a better diagnosis, care and integration of individuals with ASD.
Published: 2016
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29. 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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29 results on '"ANR-10-LABX-0013,GENMED,Medical Genomics(2010)"'

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

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

3. Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish

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

5. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

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

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

8. Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

9. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

10. The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

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

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

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

14. Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

15. A novel rare c.-39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codone

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

17. Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume

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

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

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

21. Experimenting with reproducibility: a case study of robustness in bioinformatics

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

23. Genome-Wide Association Study Identifies a Novel Genetic Risk Factor for Recurrent Venous Thrombosis

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

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

26. Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus

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

28. Current knowledge on the genetics of autism and propositions for future research

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

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

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