Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome / Bhismadev CHAKRABARTI in Autism Research, 2-3 (June 2009)  

Public ISBD [article]  inAutism Research > 2-3 (June 2009) . - p.157-177 Titre : Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Bhismadev CHAKRABARTI, Auteur ; Simon BARON-COHEN, Auteur ; Sally WHEELWRIGHT, Auteur ; Carrie ALLISON, Auteur ; F. DUDBRIDGE, Auteur ; G. HILL-CAWTHORNE, Auteur ; Sharmila BANERJEE-BASU, Auteur ; Lindsey KENT, Auteur Année de publication : 2009 Article en page(s) : p.157-177 Langues : Anglais (eng) Mots-clés : genetics Asperger-syndrome autism empathy autistic-traits visual-search emotion-recognition SNP broader-autism-phenotype Index. décimale : PER Périodiques Résumé : Genetic studies of autism spectrum conditions (ASC) have mostly focused on the low functioning severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common (1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a high-functioning subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping. En ligne : http://dx.doi.org/10.1002/aur.80 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=937 [article] Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome [Texte imprimé et/ou numérique] / Bhismadev CHAKRABARTI, Auteur ; Simon BARON-COHEN, Auteur ; Sally WHEELWRIGHT, Auteur ; Carrie ALLISON, Auteur ; F. DUDBRIDGE, Auteur ; G. HILL-CAWTHORNE, Auteur ; Sharmila BANERJEE-BASU, Auteur ; Lindsey KENT, Auteur . - 2009 . - p.157-177. Langues : Anglais (eng) in Autism Research > 2-3 (June 2009) . - p.157-177 Mots-clés : genetics Asperger-syndrome autism empathy autistic-traits visual-search emotion-recognition SNP broader-autism-phenotype Index. décimale : PER Périodiques Résumé : Genetic studies of autism spectrum conditions (ASC) have mostly focused on the low functioning severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common (1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a high-functioning subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping. En ligne : http://dx.doi.org/10.1002/aur.80 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=937

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation / A. SAFFARI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 38 p. 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 [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

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