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Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression / Emily L. CASANOVA in Molecular Autism, 7 (2016)
[article]
Titre : Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression Type de document : Texte imprimé et/ou numérique Auteurs : Emily L. CASANOVA, Auteur ; J. L. SHARP, Auteur ; H. CHAKRABORTY, Auteur ; N. S. SUMI, Auteur ; Manuel F. CASANOVA, Auteur Article en page(s) : 18p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/epidemiology/genetics/psychology Autistic Disorder/epidemiology/genetics/psychology Body Patterning/genetics Cell Nucleus/metabolism Chromatin Assembly and Disassembly/genetics Comorbidity Databases, Genetic Epigenomics Epilepsy/epidemiology/genetics/psychology Gene Expression Regulation Gene Ontology Genetic Association Studies Humans Intellectual Disability/epidemiology/genetics Nerve Tissue Proteins/genetics/physiology Neurogenesis/genetics Nuclear Proteins/genetics/physiology Penetrance Protein Interaction Maps/genetics Risk Syndrome Body patterning Chromatin assembly and disassembly Epilepsy Mental retardation Regulation of gene expression Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions. En ligne : http://dx.doi.org/10.1186/s13229-016-0082-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 18p.[article] Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression [Texte imprimé et/ou numérique] / Emily L. CASANOVA, Auteur ; J. L. SHARP, Auteur ; H. CHAKRABORTY, Auteur ; N. S. SUMI, Auteur ; Manuel F. CASANOVA, Auteur . - 18p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 18p.
Mots-clés : Autism Spectrum Disorder/epidemiology/genetics/psychology Autistic Disorder/epidemiology/genetics/psychology Body Patterning/genetics Cell Nucleus/metabolism Chromatin Assembly and Disassembly/genetics Comorbidity Databases, Genetic Epigenomics Epilepsy/epidemiology/genetics/psychology Gene Expression Regulation Gene Ontology Genetic Association Studies Humans Intellectual Disability/epidemiology/genetics Nerve Tissue Proteins/genetics/physiology Neurogenesis/genetics Nuclear Proteins/genetics/physiology Penetrance Protein Interaction Maps/genetics Risk Syndrome Body patterning Chromatin assembly and disassembly Epilepsy Mental retardation Regulation of gene expression Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions. En ligne : http://dx.doi.org/10.1186/s13229-016-0082-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation / A. SAFFARI in Molecular Autism, 10 (2019)
[article]
Titre : RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation Type de document : Texte imprimé et/ou numérique Auteurs : A. SAFFARI, Auteur ; M. ARNO, Auteur ; E. NASSER, Auteur ; A. RONALD, Auteur ; C. C. Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; J. MILL, Auteur ; F. DUDBRIDGE, Auteur ; E. L. MEABURN, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder DNA methylation Discordance Epigenomics Gene expression Immune MZ twins RNA-seq Transcriptomics Index. décimale : PER Périodiques Résumé : Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals. En ligne : http://dx.doi.org/10.1186/s13229-019-0285-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414
in Molecular Autism > 10 (2019) . - 38 p.[article] RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation [Texte imprimé et/ou numérique] / A. SAFFARI, Auteur ; M. ARNO, Auteur ; E. NASSER, Auteur ; A. RONALD, Auteur ; C. C. Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; J. MILL, Auteur ; F. DUDBRIDGE, Auteur ; E. L. MEABURN, Auteur . - 38 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 38 p.
Mots-clés : Autism spectrum disorder DNA methylation Discordance Epigenomics Gene expression Immune MZ twins RNA-seq Transcriptomics Index. décimale : PER Périodiques Résumé : Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals. En ligne : http://dx.doi.org/10.1186/s13229-019-0285-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414