3 recherche sur le mot-clé 'Schizophrenia/genetics'

Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia / Ana Maria PORTUGAL in Journal of Child Psychology and Psychiatry, 63-9 (September 2022)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 63-9 (September 2022) . - p.1068-1077 Titre : Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia Type de document : Texte imprimé et/ou numérique Auteurs : Ana Maria PORTUGAL, Auteur ; Mark J. TAYLOR, Auteur ; Charlotte VIKTORSSON, Auteur ; Pär NYSTROM, Auteur ; Danyang LI, Auteur ; Kristiina TAMMIMIES, Auteur ; Angelica RONALD, Auteur ; Terje FALCK-YTTER, Auteur Article en page(s) : p.1068-1077 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder  Depressive Disorder, Major  Humans  Infant  Pupil/physiology  Reflex, Pupillary/physiology  Schizophrenia/genetics  Pupillometry  infancy  polygenic risk scores  pupillary light reflex  schizophrenia  twin design Index. décimale : PER Périodiques Résumé : BACKGROUND: Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions. METHODS: We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome-wide polygenic scores (GPSs). RESULTS: Univariate twin modelling showed high heritability at 5months for both pupil size (h(2) =.64) and constriction in response to light (h(2) =.62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (r(G) =.38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (Î2=.15, p=.024), while there was no significant association with the GPS for autism or any other GPSs. CONCLUSIONS: This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life. En ligne : http://dx.doi.org/10.1111/jcpp.13564 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=486 [article] Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia [Texte imprimé et/ou numérique] / Ana Maria PORTUGAL, Auteur ; Mark J. TAYLOR, Auteur ; Charlotte VIKTORSSON, Auteur ; Pär NYSTROM, Auteur ; Danyang LI, Auteur ; Kristiina TAMMIMIES, Auteur ; Angelica RONALD, Auteur ; Terje FALCK-YTTER, Auteur . - p.1068-1077. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 63-9 (September 2022) . - p.1068-1077 Mots-clés : Autism Spectrum Disorder  Depressive Disorder, Major  Humans  Infant  Pupil/physiology  Reflex, Pupillary/physiology  Schizophrenia/genetics  Pupillometry  infancy  polygenic risk scores  pupillary light reflex  schizophrenia  twin design Index. décimale : PER Périodiques Résumé : BACKGROUND: Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions. METHODS: We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome-wide polygenic scores (GPSs). RESULTS: Univariate twin modelling showed high heritability at 5months for both pupil size (h(2) =.64) and constriction in response to light (h(2) =.62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (r(G) =.38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (Î2=.15, p=.024), while there was no significant association with the GPS for autism or any other GPSs. CONCLUSIONS: This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life. En ligne : http://dx.doi.org/10.1111/jcpp.13564 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=486

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells / P. WANG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 11p. Titre : CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells Type de document : Texte imprimé et/ou numérique Auteurs : P. WANG, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; M. KIRSCHENBAUM, Auteur ; C. BAYRAK, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur Article en page(s) : 11p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Bipolar Disorder/genetics  CRISPR-Cas Systems  Cell Differentiation  Cells, Cultured  DNA-Binding Proteins/*genetics  Gene Expression Profiling/*methods  Gene Expression Regulation  Gene Knockout Techniques  *Gene Regulatory Networks  Humans  Induced Pluripotent Stem Cells/*cytology  Mental Disorders/*genetics  Mutation  Organoids/*cytology  Schizophrenia/genetics  Sequence Analysis, RNA/*methods  Telencephalon/*cytology  Transcription Factors/*genetics  *Autism  *Beta-catenin  *Bipolar disorder  *Cancer  *Dlx6-as1  *Distal-less homeobox  *Gabaergic  *Hmga2  *Schizophrenia  *Tcf4  *Wnt  *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells [Texte imprimé et/ou numérique] / P. WANG, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; M. KIRSCHENBAUM, Auteur ; C. BAYRAK, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur . - 11p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 11p. Mots-clés : Autism Spectrum Disorder/genetics  Bipolar Disorder/genetics  CRISPR-Cas Systems  Cell Differentiation  Cells, Cultured  DNA-Binding Proteins/*genetics  Gene Expression Profiling/*methods  Gene Expression Regulation  Gene Knockout Techniques  *Gene Regulatory Networks  Humans  Induced Pluripotent Stem Cells/*cytology  Mental Disorders/*genetics  Mutation  Organoids/*cytology  Schizophrenia/genetics  Sequence Analysis, RNA/*methods  Telencephalon/*cytology  Transcription Factors/*genetics  *Autism  *Beta-catenin  *Bipolar disorder  *Cancer  *Dlx6-as1  *Distal-less homeobox  *Gabaergic  *Hmga2  *Schizophrenia  *Tcf4  *Wnt  *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Genetic and phenotypic heterogeneity in early neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study / Laura HEGEMANN in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 25p. Titre : Genetic and phenotypic heterogeneity in early neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study Type de document : Texte imprimé et/ou numérique Auteurs : Laura HEGEMANN, Auteur ; Elizabeth C. CORFIELD, Auteur ; Adrian Dahl ASKELUND, Auteur ; Andrea G. ALLEGRINI, Auteur ; Ragna Bugge ASKELAND, Auteur ; Angelica RONALD, Auteur ; Helga ASK, Auteur ; Beate ST POURCAIN, Auteur ; Ole A. ANDREASSEN, Auteur ; Laurie J. HANNIGAN, Auteur ; Alexandra. HAVDAHL, Auteur Article en page(s) : 25p. Langues : Anglais (eng) Mots-clés : Humans  Norway  Female  Male  Phenotype  Child, Preschool  Cohort Studies  Neurodevelopmental Disorders/genetics/diagnosis  Mothers  Autistic Disorder/genetics  Genetic Predisposition to Disease  Adult  Fathers  Genome-Wide Association Study  Attention Deficit Disorder with Hyperactivity/genetics/diagnosis  Schizophrenia/genetics  Genetic Heterogeneity Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations. METHODS: In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708-58,630) using maternal reports on 76 items assessing children's motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. RESULTS: We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items r(g) range = -?0.27-0.78), ADHD (items r(g) range = -?0.40-1), and schizophrenia (items r(g) range = -?0.24-0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other. CONCLUSIONS: These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs. En ligne : https://dx.doi.org/10.1186/s13229-024-00599-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Genetic and phenotypic heterogeneity in early neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study [Texte imprimé et/ou numérique] / Laura HEGEMANN, Auteur ; Elizabeth C. CORFIELD, Auteur ; Adrian Dahl ASKELUND, Auteur ; Andrea G. ALLEGRINI, Auteur ; Ragna Bugge ASKELAND, Auteur ; Angelica RONALD, Auteur ; Helga ASK, Auteur ; Beate ST POURCAIN, Auteur ; Ole A. ANDREASSEN, Auteur ; Laurie J. HANNIGAN, Auteur ; Alexandra. HAVDAHL, Auteur . - 25p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 25p. Mots-clés : Humans  Norway  Female  Male  Phenotype  Child, Preschool  Cohort Studies  Neurodevelopmental Disorders/genetics/diagnosis  Mothers  Autistic Disorder/genetics  Genetic Predisposition to Disease  Adult  Fathers  Genome-Wide Association Study  Attention Deficit Disorder with Hyperactivity/genetics/diagnosis  Schizophrenia/genetics  Genetic Heterogeneity Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations. METHODS: In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708-58,630) using maternal reports on 76 items assessing children's motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. RESULTS: We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items r(g) range = -?0.27-0.78), ADHD (items r(g) range = -?0.40-1), and schizophrenia (items r(g) range = -?0.24-0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other. CONCLUSIONS: These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs. En ligne : https://dx.doi.org/10.1186/s13229-024-00599-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538