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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 TH1/Treg ratio may be a marker of autism in children with immune dysfunction / Zu-Qing NIE in Research in Autism Spectrum Disorders, 101 (March 2023)
[article]
Titre : TH1/Treg ratio may be a marker of autism in children with immune dysfunction Type de document : Texte imprimé et/ou numérique Auteurs : Zu-Qing NIE, Auteur ; Dong HAN, Auteur ; Kun ZHANG, Auteur ; Meng LI, Auteur ; Ho-Keun KWON, Auteur ; Sin-Hyeog IM, Auteur ; Li XU, Auteur ; Ji-chun YANG, Auteur ; Zhi-Wei LI, Auteur ; Xin-Wei HUANG, Auteur ; Jie WEN, Auteur ; Yang SHU-JUN, Auteur ; Fang YIN, Auteur ; Chen SHEN, Auteur ; Paul ASHWOOD, Auteur ; Chuan-Yuan KANG, Auteur ; Xia CAO, Auteur Article en page(s) : 102085 Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD) T cells Regulation Cytokines T helper T helper-1 T regulatory cell Neurodevelopment Immune Index. décimale : PER Périodiques Résumé : Evidence suggests a link between autism spectrum disorder (ASD), behavioral symptoms in the context of ASD, and presence of an altered immune function. Several studies have highlighted differences in T-lymphocyte subpopulations, their activation status, and their response to stimulation in children and adults with ASD. These T cell abnormalities have often been associated with more impaired behaviors. However, few studies have attempted to address whether T cell subsets have the potential to serve as biomarkers in ASD. Moreover, although many studies have been performed in Western populations, few (if any) have been performed in Asian populations in mainland China. In this study we used intracellular cytokine flow cytometry to assess the frequencies of CD4+ T-cell subpopulations (T-helper (TH) 1, TH2, TH17, Foxp3+ regulatory T cells (Treg) as well as CD8+, subpopulations of T cytotoxic (TC) 1, TC2, and TC17 in 82 children with ASD and 50 healthy typical developing children from the Second Affiliated Hospital of Kunming Medical University of Yunnan province. To further elucidate immune status cytokine levels were also measured in the plasma and serum using a bead-based cytokine assay. Our results showed that the frequency of circulating Treg cells and the levels of active TGF-Î21 in plasma were lower in children with ASD than in healthy controls. In contrast, the frequencies of TH1, TH2, TH17 and TC1 cells were increased. Proinflammatory cytokine levels of TNF-Î+, IL-4, IL-5 and IL-17A were higher in the plasma of children with ASD compared to typical controls. We also found an association between the severity of behavior impairments in ASD children and altered immune responses as measured using the effector T cell responses and regulatory responses (using Teff/Treg ratios). Higher the Teff/Treg ratios, were associated with more severe problematic behavioral symptoms. Further, the potential biomarker relevance of Teff/Treg ratio was evaluated by the receiver operating characteristics curve. Data suggests that high TH1/Treg cell ratios could also be used as a potential marker for the diagnosis of children with ASD. Overall, our data suggest an imbalance in inflammatory and regulatory immune responses in ASD. Ratios of inflammatory/regulatory cells or cell frequencies such as Teff/Treg cells may be useful biomarkers for children with ASD with immune dysfunction. En ligne : https://doi.org/10.1016/j.rasd.2022.102085 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=492
in Research in Autism Spectrum Disorders > 101 (March 2023) . - 102085[article] TH1/Treg ratio may be a marker of autism in children with immune dysfunction [Texte imprimé et/ou numérique] / Zu-Qing NIE, Auteur ; Dong HAN, Auteur ; Kun ZHANG, Auteur ; Meng LI, Auteur ; Ho-Keun KWON, Auteur ; Sin-Hyeog IM, Auteur ; Li XU, Auteur ; Ji-chun YANG, Auteur ; Zhi-Wei LI, Auteur ; Xin-Wei HUANG, Auteur ; Jie WEN, Auteur ; Yang SHU-JUN, Auteur ; Fang YIN, Auteur ; Chen SHEN, Auteur ; Paul ASHWOOD, Auteur ; Chuan-Yuan KANG, Auteur ; Xia CAO, Auteur . - 102085.
Langues : Anglais (eng)
in Research in Autism Spectrum Disorders > 101 (March 2023) . - 102085
Mots-clés : Autism spectrum disorder (ASD) T cells Regulation Cytokines T helper T helper-1 T regulatory cell Neurodevelopment Immune Index. décimale : PER Périodiques Résumé : Evidence suggests a link between autism spectrum disorder (ASD), behavioral symptoms in the context of ASD, and presence of an altered immune function. Several studies have highlighted differences in T-lymphocyte subpopulations, their activation status, and their response to stimulation in children and adults with ASD. These T cell abnormalities have often been associated with more impaired behaviors. However, few studies have attempted to address whether T cell subsets have the potential to serve as biomarkers in ASD. Moreover, although many studies have been performed in Western populations, few (if any) have been performed in Asian populations in mainland China. In this study we used intracellular cytokine flow cytometry to assess the frequencies of CD4+ T-cell subpopulations (T-helper (TH) 1, TH2, TH17, Foxp3+ regulatory T cells (Treg) as well as CD8+, subpopulations of T cytotoxic (TC) 1, TC2, and TC17 in 82 children with ASD and 50 healthy typical developing children from the Second Affiliated Hospital of Kunming Medical University of Yunnan province. To further elucidate immune status cytokine levels were also measured in the plasma and serum using a bead-based cytokine assay. Our results showed that the frequency of circulating Treg cells and the levels of active TGF-Î21 in plasma were lower in children with ASD than in healthy controls. In contrast, the frequencies of TH1, TH2, TH17 and TC1 cells were increased. Proinflammatory cytokine levels of TNF-Î+, IL-4, IL-5 and IL-17A were higher in the plasma of children with ASD compared to typical controls. We also found an association between the severity of behavior impairments in ASD children and altered immune responses as measured using the effector T cell responses and regulatory responses (using Teff/Treg ratios). Higher the Teff/Treg ratios, were associated with more severe problematic behavioral symptoms. Further, the potential biomarker relevance of Teff/Treg ratio was evaluated by the receiver operating characteristics curve. Data suggests that high TH1/Treg cell ratios could also be used as a potential marker for the diagnosis of children with ASD. Overall, our data suggest an imbalance in inflammatory and regulatory immune responses in ASD. Ratios of inflammatory/regulatory cells or cell frequencies such as Teff/Treg cells may be useful biomarkers for children with ASD with immune dysfunction. En ligne : https://doi.org/10.1016/j.rasd.2022.102085 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=492 Alterations in plasma cytokine levels in chinese children with autism spectrum disorder / C. C. HU in Autism Research, 11-7 (July 2018)
[article]
Titre : Alterations in plasma cytokine levels in chinese children with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : C. C. HU, Auteur ; X. XU, Auteur ; G. L. XIONG, Auteur ; Q. XU, Auteur ; B. R. ZHOU, Auteur ; C. Y. LI, Auteur ; Q. QIN, Auteur ; C. X. LIU, Auteur ; H. P. LI, Auteur ; Y. J. SUN, Auteur ; X. YU, Auteur Article en page(s) : p.989-999 Langues : Anglais (eng) Mots-clés : TGF-beta1 TNF-alpha cytokine eotaxin immune neuroinflammation Index. décimale : PER Périodiques Résumé : Genetic alterations, together with environmental risk factors during infancy and childhood, contribute significantly to the etiology of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental condition characterized by impairments in social interaction and restricted, repetitive behaviors. Mounting evidence points to a critical contribution of immunological risk factors to the development of ASD. By affecting multiple neurodevelopmental processes, immune system dysfunction could act as a point of convergence between genetics and environmental factors in ASD. Previous studies have shown altered cytokine levels in individuals with ASD, but research in Asian populations are limited. Here, we measured the plasma levels of 11 candidate cytokines in ASD and typically developing (TD) children. The cohort included 41 TD children and 87 children with ASD, aged 1-6 years. We found that as compared to the TD group, children with ASD had higher plasma levels of Eotaxin, TGF-beta1 and TNF-alpha. The increase in TGF-beta1 level was most significant in males, while the increase in Eotaxin was most significant in females. Eotaxin level negatively correlated with the social affect score (SA) in ADOS, while TNF-alpha level positively correlated with total development quotient (DQ), measured using GMDS. These pilot findings suggest potentially important roles of Eotaxin, TGF-beta1 and TNF-alpha in ASD in the Chinese population. Autism Res 2018, 11: 989-999. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Alteration of immune system function is an important risk factor for autism spectrum disorder (ASD). Here we found that the levels of cytokines, including Eotaxin, TGF-beta1 and TNF-alpha, are elevated in Chinese children with ASD, as compared to typically developing children. The change in TGF-beta1 level was most prominent in boys, while that of Eotaxin was more significant in girls. These results provide evidence for changes in cytokine profile in Chinese children with ASD. En ligne : http://dx.doi.org/10.1002/aur.1940 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=366
in Autism Research > 11-7 (July 2018) . - p.989-999[article] Alterations in plasma cytokine levels in chinese children with autism spectrum disorder [Texte imprimé et/ou numérique] / C. C. HU, Auteur ; X. XU, Auteur ; G. L. XIONG, Auteur ; Q. XU, Auteur ; B. R. ZHOU, Auteur ; C. Y. LI, Auteur ; Q. QIN, Auteur ; C. X. LIU, Auteur ; H. P. LI, Auteur ; Y. J. SUN, Auteur ; X. YU, Auteur . - p.989-999.
Langues : Anglais (eng)
in Autism Research > 11-7 (July 2018) . - p.989-999
Mots-clés : TGF-beta1 TNF-alpha cytokine eotaxin immune neuroinflammation Index. décimale : PER Périodiques Résumé : Genetic alterations, together with environmental risk factors during infancy and childhood, contribute significantly to the etiology of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental condition characterized by impairments in social interaction and restricted, repetitive behaviors. Mounting evidence points to a critical contribution of immunological risk factors to the development of ASD. By affecting multiple neurodevelopmental processes, immune system dysfunction could act as a point of convergence between genetics and environmental factors in ASD. Previous studies have shown altered cytokine levels in individuals with ASD, but research in Asian populations are limited. Here, we measured the plasma levels of 11 candidate cytokines in ASD and typically developing (TD) children. The cohort included 41 TD children and 87 children with ASD, aged 1-6 years. We found that as compared to the TD group, children with ASD had higher plasma levels of Eotaxin, TGF-beta1 and TNF-alpha. The increase in TGF-beta1 level was most significant in males, while the increase in Eotaxin was most significant in females. Eotaxin level negatively correlated with the social affect score (SA) in ADOS, while TNF-alpha level positively correlated with total development quotient (DQ), measured using GMDS. These pilot findings suggest potentially important roles of Eotaxin, TGF-beta1 and TNF-alpha in ASD in the Chinese population. Autism Res 2018, 11: 989-999. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Alteration of immune system function is an important risk factor for autism spectrum disorder (ASD). Here we found that the levels of cytokines, including Eotaxin, TGF-beta1 and TNF-alpha, are elevated in Chinese children with ASD, as compared to typically developing children. The change in TGF-beta1 level was most prominent in boys, while that of Eotaxin was more significant in girls. These results provide evidence for changes in cytokine profile in Chinese children with ASD. En ligne : http://dx.doi.org/10.1002/aur.1940 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=366 Hierarchical cortical transcriptome disorganization in autism / M. V. LOMBARDO in Molecular Autism, 8 (2017)
[article]
Titre : Hierarchical cortical transcriptome disorganization in autism Type de document : Texte imprimé et/ou numérique Auteurs : M. V. LOMBARDO, Auteur ; E. COURCHESNE, Auteur ; N. E. LEWIS, Auteur ; T. PRAMPARO, Auteur Article en page(s) : 29p. Langues : Anglais (eng) Mots-clés : Autism Gene co-expression networks Immune Synapse Systems biology Transcriptome Translation Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are etiologically heterogeneous and complex. Functional genomics work has begun to identify a diverse array of dysregulated transcriptomic programs (e.g., synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning and differentiation) potentially involved in ASD brain abnormalities during childhood and adulthood. However, it remains unclear whether such diverse dysregulated pathways are independent of each other or instead reflect coordinated hierarchical systems-level pathology. METHODS: Two ASD cortical transcriptome datasets were re-analyzed using consensus weighted gene co-expression network analysis (WGCNA) to identify common co-expression modules across datasets. Linear mixed-effect models and Bayesian replication statistics were used to identify replicable differentially expressed modules. Eigengene network analysis was then utilized to identify between-group differences in how co-expression modules interact and cluster into hierarchical meta-modular organization. Protein-protein interaction analyses were also used to determine whether dysregulated co-expression modules show enhanced interactions. RESULTS: We find replicable evidence for 10 gene co-expression modules that are differentially expressed in ASD cortex. Rather than being independent non-interacting sources of pathology, these dysregulated co-expression modules work in synergy and physically interact at the protein level. These systems-level transcriptional signals are characterized by downregulation of synaptic processes coordinated with upregulation of immune/inflammation, response to other organism, catabolism, viral processes, translation, protein targeting and localization, cell proliferation, and vasculature development. Hierarchical organization of meta-modules (clusters of highly correlated modules) is also highly affected in ASD. CONCLUSIONS: These findings highlight that dysregulation of the ASD cortical transcriptome is characterized by the dysregulation of multiple coordinated transcriptional programs producing synergistic systems-level effects that cannot be fully appreciated by studying the individual component biological processes in isolation. En ligne : http://dx.doi.org/10.1186/s13229-017-0147-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 29p.[article] Hierarchical cortical transcriptome disorganization in autism [Texte imprimé et/ou numérique] / M. V. LOMBARDO, Auteur ; E. COURCHESNE, Auteur ; N. E. LEWIS, Auteur ; T. PRAMPARO, Auteur . - 29p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 29p.
Mots-clés : Autism Gene co-expression networks Immune Synapse Systems biology Transcriptome Translation Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are etiologically heterogeneous and complex. Functional genomics work has begun to identify a diverse array of dysregulated transcriptomic programs (e.g., synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning and differentiation) potentially involved in ASD brain abnormalities during childhood and adulthood. However, it remains unclear whether such diverse dysregulated pathways are independent of each other or instead reflect coordinated hierarchical systems-level pathology. METHODS: Two ASD cortical transcriptome datasets were re-analyzed using consensus weighted gene co-expression network analysis (WGCNA) to identify common co-expression modules across datasets. Linear mixed-effect models and Bayesian replication statistics were used to identify replicable differentially expressed modules. Eigengene network analysis was then utilized to identify between-group differences in how co-expression modules interact and cluster into hierarchical meta-modular organization. Protein-protein interaction analyses were also used to determine whether dysregulated co-expression modules show enhanced interactions. RESULTS: We find replicable evidence for 10 gene co-expression modules that are differentially expressed in ASD cortex. Rather than being independent non-interacting sources of pathology, these dysregulated co-expression modules work in synergy and physically interact at the protein level. These systems-level transcriptional signals are characterized by downregulation of synaptic processes coordinated with upregulation of immune/inflammation, response to other organism, catabolism, viral processes, translation, protein targeting and localization, cell proliferation, and vasculature development. Hierarchical organization of meta-modules (clusters of highly correlated modules) is also highly affected in ASD. CONCLUSIONS: These findings highlight that dysregulation of the ASD cortical transcriptome is characterized by the dysregulation of multiple coordinated transcriptional programs producing synergistic systems-level effects that cannot be fully appreciated by studying the individual component biological processes in isolation. En ligne : http://dx.doi.org/10.1186/s13229-017-0147-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330