Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

Étude expérimentale de la structure de perles sur ficelle au cours de l'étirement d'un fluide viscoélastique par holographie numérique.

International audienceViscoelastic fluids are currently used for a wide variety of applications in food, chemical, cosmetics and pharmaceutical industries. They are dilute or semi-dilute solutions of high-molecular-weight polymers. For some concentrations, the controlled stretching of the fluid leads to the formation of beads-on-string structures which are characterized by drops connected by a filament. In our case, the controlled extension of the viscoelastic fluid is achieved thanks to an in-house filament stretching device. In order to analyse the 3D dynamic of the beads-on-string structure, i.e. to measure the displacement and the velocity of the bead-like drops during and after the stretching process, we use double exposure Holographic imaging. Holography allows us to choose a 3D volume of space to capture the entire phenomenon. Thanks to Holography, we can focus on one or several planes along the optical axis in order to estimate the 2D coordinates of beads in each plane. The computation of these planes leads to a reconstructed volume where the 3D displacements of beads along the x, y and z axes can be extracted. The dynamic of beads-on-string structures may depend on several factors which are linked to the fluid properties but also to the initial state and elongation parameters. The aim of this work is to experimentally identify the factors which are appropriate to observe a repeatable beads-on-string structure before studying the influence of an orthogonal air current

Effect of a controlled air flow on a viscoelastic filament

International audienceRecent health crises have highlighted the need to better assess and prevent the risks associated with the release of potentially infectious particles into the air during human expiratory events, such as breathing, talking, sneezing, and coughing. Some of these particles originate from the stretching in the mouth of a volume of saliva, which leads to the formation of a beads-on-a-string (BOAS) structure. This structure is characteristic of the behavior of viscoelastic fluids when subjected to an elongational flow.To simulate and analyze the effect of an expiratory event on a viscoelastic filament, an experimental bench was set up to stretch a sample of polymer solution and destabilize the BOAS structure formed, by a controlled air flow. The setup is fully automated, allowing statistical measurements on a large number of samples. The dynamics of the filament as well as the released drops are observed by multi-exposure and dual-wavelength inline digital holography. This method allows us to measure the size, position and velocity of the particles in a 3D volume.The experiment presented here serves as a simple model for the atomization induced on a viscoelastic filament during a human expiratory event

Holographie in-line appliquée à l’analyse de l’étirement d’un filament viscoélastique.: Restitution optimale par analyse de la phase.

International audienceDe nombreux fluides, comme ceux de l’industrie agro-alimentaire ou pharmaceutique, sont viscoélastiques. La viscoélasticité est due à la présence de polymères dont la masse molaire est élevée en solution dans ces fluides. Pour certaines concentrations en polymères, lorsque l’on étire ces fluides, on observe l’apparition de gouttelettes (ou perles) en mouvement sur le filament. L’holographie numérique in-line est appliquée ici pour étudier la dynamique du filament et des gouttelettes en 3-D. Il faut préciser que le milieu dans lequel évoluent ces objets est faiblement perturbé (pas de gradients d’indice). L’onde de référence peut donc ici être considérée comme sphérique. Dans ces conditions, il est possible d’extraire des informations quantitatives sur la phase restituée permettant ainsi de réaliser une mise au point précise sur les images de gouttelettes ou du filament. [ ] Nous présentons le dispositif expérimental et montrons quelques exemples d’images restituées par la signature de phase. Dispositif expérimentalLe fluide viscoélastique est placé dans un dispositif mécanique d’étirement fabriqué au laboratoire. C’est un système constitué d’un support mobile qui étire le fluide et dont les paramètres d’étirage sont parfaitement contrôlés. Afin de pouvoir accéder à des informations sur la vitesse [ ], nous éclairons le fluide en étirement par une séquence de deux impulsions lasers (τ<1 µs) aux longueurs d’onde λ_V=520 nm et λ_R=660 nm. Les hologrammes sont enregistrés par un capteur CCD d’une résolution de 4096×4096 pixels de taille p=5,5 µm. Traitement des hologrammesLes hologrammes sont exploités par convolution avec le noyau de Fresnel et les images sont localisées par analyse de l’amplitude complexe restituée. Lorsque l’on s’approche du plan de mise au point d’un élément du fluide de coordonnées transversales (x_0,y_0), les variations de phase déroulée selon l’axe optique φ(x_0,y_0,z) présentent une allure asymptotique en 1/z qui permet d’extraire avec précision la coordonnée axiale z_0. La méthode ainsi que les résultats issus d’hologrammes simulés et expérimentaux sont présentés et montrent les avantages de cette technique pour une localisation 3-D précise de particules de fluides micrométriques

Étude expérimentale de la structure de perles sur ficelle au cours de l'étirement d'un fluide viscoélastique par holographie numérique.

International audienceViscoelastic fluids are currently used for a wide variety of applications in food, chemical, cosmetics and pharmaceutical industries. They are dilute or semi-dilute solutions of high-molecular-weight polymers. For some concentrations, the controlled stretching of the fluid leads to the formation of beads-on-string structures which are characterized by drops connected by a filament. In our case, the controlled extension of the viscoelastic fluid is achieved thanks to an in-house filament stretching device. In order to analyse the 3D dynamic of the beads-on-string structure, i.e. to measure the displacement and the velocity of the bead-like drops during and after the stretching process, we use double exposure Holographic imaging. Holography allows us to choose a 3D volume of space to capture the entire phenomenon. Thanks to Holography, we can focus on one or several planes along the optical axis in order to estimate the 2D coordinates of beads in each plane. The computation of these planes leads to a reconstructed volume where the 3D displacements of beads along the x, y and z axes can be extracted. The dynamic of beads-on-string structures may depend on several factors which are linked to the fluid properties but also to the initial state and elongation parameters. The aim of this work is to experimentally identify the factors which are appropriate to observe a repeatable beads-on-string structure before studying the influence of an orthogonal air current

An experimental model to setup for modeling the saliva behaviour in the oral cavity

Recent health crises have highlighted the need to better assess and prevent the risks associated with the release of potentially infectious particles into the air during human expiratory events, such as breathing, talking, sneezing, and coughing. Some of these particles originate from the stretching in the mouth of a volume of saliva, which leads to the formation of a beads-on-a-string (BOAS) structure. This structure is characteristic of the behavior of viscoelastic fluids when subjected to an elongational flow. To simulate and analyze the effect of an expiratory event on a viscoelastic filament, an experimental bench was set up to stretch a sample of polymer solution and destabilize the BOAS structure formed, by a controlled air flow. The setup is fully automated, allowing statistical measurements on a large number of samples. The dynamics of the filament as well as the released drops are observed by multi-exposure and dual-wavelength inline digital holography. This method allows us to measure the size, position, and velocity of the particles in a 3D volume. The experiment presented here serves as a simple model for the atomization induced on a viscoelastic filament during a human expiratory event

Étude de l'étirement d'un fluide viscoélastique par holographie numérique.

International audienceL'holographie numérique, dans sa configuration « in-line » est utilisée pour mesurer la position et vitesse 3D de fines gouttelettes qui se forment lorsque l’on étire un fluide viscoélastique dans des conditions bien maîtrisées. Nous présentons le dispositif utilisé pour étirer les fluides et le système d’enregistrement et de traitement des hologrammesmis en œuvre pour étudier et caractériser la dynamique tridimensionnelle des perles

Phase analysis for focus plane detection in digital inline holography: application to three-dimensional locations of drops and threads in a beads-on-a-string structure

Three-dimensional (3D) phase maps are used in a digital inline holography system to measure the coordinates of tiny particles. The phase signature, previously applied to spherical particles by Yang et al . [ Opt. Lett. 31 , 1399 ( 2006 ) OPLEDP 0146-9592 10.1364/OL.31.001399 ], is extended here to the case of an infinite cylindrical filament to determine the optimal focus plane. The practical implementation of this method is described. Simulations show that this technique provides a very efficient tool to examine the 3D coordinates of micrometric objects. A practical application is given with the investigation of the dynamics of beads-on-a-string structures under an air flow current. These structures, obtained by stretching a viscoelastic fluid element, are of particular interest in this study, since they are characterized by several quasi-spherical beads (i.e., drops) linked by a quasi-cylindrical filament (i.e., thread)