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 Auteurs : Bhismadev CHAKRABARTI, Auteur ; Simon BARON-COHEN, Auteur ; Sally WHEELWRIGHT, Auteur ; Carrie ALLISON, Auteur ; Frank 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] / Bhismadev CHAKRABARTI, Auteur ; Simon BARON-COHEN, Auteur ; Sally WHEELWRIGHT, Auteur ; Carrie ALLISON, Auteur ; Frank 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

Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes / Jean-Baptiste PINGAULT in Journal of Child Psychology and Psychiatry, 63-10 (October 2022)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 63-10 (October 2022) . - p.1125-1139 Titre : Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes Type de document : texte imprimé Auteurs : Jean-Baptiste PINGAULT, Auteur ; Andrea G. ALLEGRINI, Auteur ; Tracy ODIGIE, Auteur ; Leonard FRACH, Auteur ; Jessie R. BALDWIN, Auteur ; Frühling V. RIJSDIJK, Auteur ; Frank DUDBRIDGE, Auteur Année de publication : 2022 Article en page(s) : p.1125-1139 Langues : Anglais (eng) Mots-clés : Cohort Studies  Environmental Exposure/adverse effects  Genetic Predisposition to Disease  Genome-Wide Association Study  Humans  Midazolam  Multifactorial Inheritance  Phenotype  Polygenic scores  biases  environment  epidemiology  phenotypes Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic influences are ubiquitous as virtually all phenotypes and most exposures typically classified as environmental have been found to be heritable. A polygenic score summarises the associations between millions of genetic variants and an outcome in a single value for each individual. Ever lowering costs have enabled the genotyping of many samples relevant to child psychology and psychiatry research, including cohort studies, leading to the proliferation of polygenic score studies. It is tempting to assume that associations detected between polygenic scores and phenotypes in those studies only reflect genetic effects. However, such associations can reflect many pathways (e.g. via environmental mediation) and biases. METHODS: Here, we provide a comprehensive overview of the many reasons why associations between polygenic scores, environmental exposures, and phenotypes exist. We include formal representations of common analyses in polygenic score studies using structural equation modelling. We derive biases, provide illustrative empirical examples and, when possible, mention steps that can be taken to alleviate those biases. RESULTS: Structural equation models and derivations show the many complexities arising from jointly modelling polygenic scores with environmental exposures and phenotypes. Counter-intuitive examples include that: (a) associations between polygenic scores and phenotypes may exist even in the absence of direct genetic effects; (b) associations between child polygenic scores and environmental exposures can exist in the absence of evocative/active gene-environment correlations; and (c) adjusting an exposure-outcome association for a polygenic score can increase rather than decrease bias. CONCLUSIONS: Strikingly, using polygenic scores may, in some cases, lead to more bias than not using them. Appropriately conducting and interpreting polygenic score studies thus requires researchers in child psychology and psychiatry and beyond to be versed in both epidemiological and genetic methods or build on interdisciplinary collaborations. En ligne : http://dx.doi.org/10.1111/jcpp.13607 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=486 [article] Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes [texte imprimé] / Jean-Baptiste PINGAULT, Auteur ; Andrea G. ALLEGRINI, Auteur ; Tracy ODIGIE, Auteur ; Leonard FRACH, Auteur ; Jessie R. BALDWIN, Auteur ; Frühling V. RIJSDIJK, Auteur ; Frank DUDBRIDGE, Auteur . - 2022 . - p.1125-1139. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 63-10 (October 2022) . - p.1125-1139 Mots-clés : Cohort Studies  Environmental Exposure/adverse effects  Genetic Predisposition to Disease  Genome-Wide Association Study  Humans  Midazolam  Multifactorial Inheritance  Phenotype  Polygenic scores  biases  environment  epidemiology  phenotypes Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic influences are ubiquitous as virtually all phenotypes and most exposures typically classified as environmental have been found to be heritable. A polygenic score summarises the associations between millions of genetic variants and an outcome in a single value for each individual. Ever lowering costs have enabled the genotyping of many samples relevant to child psychology and psychiatry research, including cohort studies, leading to the proliferation of polygenic score studies. It is tempting to assume that associations detected between polygenic scores and phenotypes in those studies only reflect genetic effects. However, such associations can reflect many pathways (e.g. via environmental mediation) and biases. METHODS: Here, we provide a comprehensive overview of the many reasons why associations between polygenic scores, environmental exposures, and phenotypes exist. We include formal representations of common analyses in polygenic score studies using structural equation modelling. We derive biases, provide illustrative empirical examples and, when possible, mention steps that can be taken to alleviate those biases. RESULTS: Structural equation models and derivations show the many complexities arising from jointly modelling polygenic scores with environmental exposures and phenotypes. Counter-intuitive examples include that: (a) associations between polygenic scores and phenotypes may exist even in the absence of direct genetic effects; (b) associations between child polygenic scores and environmental exposures can exist in the absence of evocative/active gene-environment correlations; and (c) adjusting an exposure-outcome association for a polygenic score can increase rather than decrease bias. CONCLUSIONS: Strikingly, using polygenic scores may, in some cases, lead to more bias than not using them. Appropriately conducting and interpreting polygenic score studies thus requires researchers in child psychology and psychiatry and beyond to be versed in both epidemiological and genetic methods or build on interdisciplinary collaborations. En ligne : http://dx.doi.org/10.1111/jcpp.13607 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=486

Research Review: Polygenic methods and their application to psychiatric traits / Naomi R. WRAY in Journal of Child Psychology and Psychiatry, 55-10 (October 2014)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 55-10 (October 2014) . - p.1068-1087 Titre : Research Review: Polygenic methods and their application to psychiatric traits Type de document : texte imprimé Auteurs : Naomi R. WRAY, Auteur ; Sang Hong LEE, Auteur ; Divya MEHTA, Auteur ; Anna A.E. VINKHUYZEN, Auteur ; Frank DUDBRIDGE, Auteur ; Christel M. MIDDELDORP, Auteur Article en page(s) : p.1068-1087 Langues : Anglais (eng) Mots-clés : Polygenic risk scoring  genome-wide association studies  psychiatric disorders  heritability  SNP analyses  disease traits Index. décimale : PER Périodiques Résumé : Background Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. Methods and scope We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Findings Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Conclusions Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors. En ligne : http://dx.doi.org/10.1111/jcpp.12295 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=238 [article] Research Review: Polygenic methods and their application to psychiatric traits [texte imprimé] / Naomi R. WRAY, Auteur ; Sang Hong LEE, Auteur ; Divya MEHTA, Auteur ; Anna A.E. VINKHUYZEN, Auteur ; Frank DUDBRIDGE, Auteur ; Christel M. MIDDELDORP, Auteur . - p.1068-1087. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 55-10 (October 2014) . - p.1068-1087 Mots-clés : Polygenic risk scoring  genome-wide association studies  psychiatric disorders  heritability  SNP analyses  disease traits Index. décimale : PER Périodiques Résumé : Background Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. Methods and scope We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Findings Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Conclusions Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors. En ligne : http://dx.doi.org/10.1111/jcpp.12295 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=238

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation / Ayden 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 Auteurs : Ayden SAFFARI, Auteur ; Matt ARNO, Auteur ; Eric NASSER, Auteur ; Angelica RONALD, Auteur ; Chloe C.Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; Jonathan MILL, Auteur ; Frank DUDBRIDGE, Auteur ; Emma 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] / Ayden SAFFARI, Auteur ; Matt ARNO, Auteur ; Eric NASSER, Auteur ; Angelica RONALD, Auteur ; Chloe C.Y. WONG, Auteur ; Leonard C. SCHALKWYK, Auteur ; Jonathan MILL, Auteur ; Frank DUDBRIDGE, Auteur ; Emma 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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