Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits / A. MASSRALI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 31 p. Titre : Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits Type de document : Texte imprimé et/ou numérique Auteurs : A. MASSRALI, Auteur ; H. BRUNEL, Auteur ; E. HANNON, Auteur ; C. WONG, Auteur ; Simon BARON-COHEN, Auteur ; V. WARRIER, Auteur Article en page(s) : 31 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Previous studies have identified differences in DNA methylation in autistic individuals compared to neurotypical individuals. Yet, it is unclear if this extends to autistic traits-subclinical manifestation of autism features in the general population. Here, we investigate the association between DNA methylation at birth (cord blood), and scores on the Social and Communication Disorders Checklist (SCDC), a measure of autistic traits, in 701 8-year-olds, by conducting a methylome-wide association study (MWAS). We did not identify significant CpGs associated with SCDC. The most significant CpG site was cg14379490, on chromosome 9 (MWAS beta = - 1.78 +/- 0.35, p value = 5.34 x 10 (-7) ). Using methylation data for autism in peripheral tissues, we did not identify a significant concordance in effect direction of CpGs with p value < 10(-4) in the SCDC MWAS (binomial sign test, p value > 0.5). In contrast, using methylation data for autism from post-mortem brain tissues, we identify a significant concordance in effect direction of CpGs with a p value < 10(-4) in the SCDC MWAS (binomial sign test, p value = 0.004). Supporting this, we observe an enrichment for genes that are dysregulated in the post-mortem autism brain (one-sided Wilcoxon rank-sum test, p value = 6.22 x 10(-5)). Finally, integrating genome-wide association study (GWAS) data for autism (n = 46,350) with mQTL maps from cord-blood (n = 771), we demonstrate that mQTLs of CpGs associated with SCDC scores at p value thresholds of 0.01 and 0.005 are significantly shifted toward lower p values in the GWAS for autism (p < 5 x 10(-3)). We provide additional support for this using a GWAS of SCDC, and demonstrate a lack of enrichment in a GWAS of Alzheimer's disease. Our results highlight the shared cross-tissue methylation architecture of autism and autistic traits, and demonstrate that mQTLs associated with differences in DNA methylation associated with childhood autistic traits are enriched for common genetic variants associated with autism and autistic traits. En ligne : https://dx.doi.org/10.1186/s13229-019-0279-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408 [article] Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits [Texte imprimé et/ou numérique] / A. MASSRALI, Auteur ; H. BRUNEL, Auteur ; E. HANNON, Auteur ; C. WONG, Auteur ; Simon BARON-COHEN, Auteur ; V. WARRIER, Auteur . - 31 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 31 p. Index. décimale : PER Périodiques Résumé : Previous studies have identified differences in DNA methylation in autistic individuals compared to neurotypical individuals. Yet, it is unclear if this extends to autistic traits-subclinical manifestation of autism features in the general population. Here, we investigate the association between DNA methylation at birth (cord blood), and scores on the Social and Communication Disorders Checklist (SCDC), a measure of autistic traits, in 701 8-year-olds, by conducting a methylome-wide association study (MWAS). We did not identify significant CpGs associated with SCDC. The most significant CpG site was cg14379490, on chromosome 9 (MWAS beta = - 1.78 +/- 0.35, p value = 5.34 x 10 (-7) ). Using methylation data for autism in peripheral tissues, we did not identify a significant concordance in effect direction of CpGs with p value < 10(-4) in the SCDC MWAS (binomial sign test, p value > 0.5). In contrast, using methylation data for autism from post-mortem brain tissues, we identify a significant concordance in effect direction of CpGs with a p value < 10(-4) in the SCDC MWAS (binomial sign test, p value = 0.004). Supporting this, we observe an enrichment for genes that are dysregulated in the post-mortem autism brain (one-sided Wilcoxon rank-sum test, p value = 6.22 x 10(-5)). Finally, integrating genome-wide association study (GWAS) data for autism (n = 46,350) with mQTL maps from cord-blood (n = 771), we demonstrate that mQTLs of CpGs associated with SCDC scores at p value thresholds of 0.01 and 0.005 are significantly shifted toward lower p values in the GWAS for autism (p < 5 x 10(-3)). We provide additional support for this using a GWAS of SCDC, and demonstrate a lack of enrichment in a GWAS of Alzheimer's disease. Our results highlight the shared cross-tissue methylation architecture of autism and autistic traits, and demonstrate that mQTLs associated with differences in DNA methylation associated with childhood autistic traits are enriched for common genetic variants associated with autism and autistic traits. En ligne : https://dx.doi.org/10.1186/s13229-019-0279-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408

The oxytocin receptor gene predicts brain activity during an emotion recognition task in autism / F. UZEFOVSKY in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 12 p. Titre : The oxytocin receptor gene predicts brain activity during an emotion recognition task in autism Type de document : Texte imprimé et/ou numérique Auteurs : F. UZEFOVSKY, Auteur ; Richard A. I. BETHLEHEM, Auteur ; S. SHAMAY-TSOORY, Auteur ; A. RUIGROK, Auteur ; R. HOLT, Auteur ; M. SPENCER, Auteur ; L. CHURA, Auteur ; V. WARRIER, Auteur ; Bhismadev CHAKRABARTI, Auteur ; Edward T. BULLMORE, Auteur ; J. SUCKLING, Auteur ; D. FLORIS, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 12 p. Langues : Anglais (eng) Mots-clés : Autism  Imaging genetics  Oxytocin receptor  Supramarginal gyrus  fMRI  the relevant national and institutional committees on human experimentation and  with the Declaration of Helsinki of 1975, as revised in 2008.Not applicable.The  authors declare that they have no competing interests.Springer Nature remains  neutral with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism is a highly varied and heritable neurodevelopmental condition, and common variants explain approximately 50% of the genetic variance of autism. One of the genes implicated in autism is the oxytocin receptor (OXTR). The current study combined genetic and brain imaging (fMRI) data to examine the moderating effect of genotype on the association between diagnosis and brain activity in response to a test of cognitive empathy. Methods: Participants were adolescents (mean age = 14.7 +/- 1.7) who were genotyped for single nucleotide polymorphisms (SNPs) within the OXTR and underwent functional brain imaging while completing the adolescent version of the 'Reading the Mind in the Eyes' Test (Eyes Test). Results: Two (rs2254298, rs53576) of the five OXTR SNPs examined were significantly associated with brain activity during the Eyes Test, and three of the SNPs (rs2254298, rs53576, rs2268491) interacted with diagnostic status to predict brain activity. All of the effects localized to the right supramarginal gyrus (rSMG) and an overlap analysis revealed a large overlap of the effects. An exploratory analysis showed that activity within an anatomically defined rSMG and genotype can predict diagnostic status with reasonable accuracy. Conclusions: This is one of the first studies to investigate OXTR and brain function in autism. The findings suggest a neurogenetic mechanism by which OXTR-dependent activity within the rSMG is related to the aetiology of autism. En ligne : https://dx.doi.org/10.1186/s13229-019-0258-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] The oxytocin receptor gene predicts brain activity during an emotion recognition task in autism [Texte imprimé et/ou numérique] / F. UZEFOVSKY, Auteur ; Richard A. I. BETHLEHEM, Auteur ; S. SHAMAY-TSOORY, Auteur ; A. RUIGROK, Auteur ; R. HOLT, Auteur ; M. SPENCER, Auteur ; L. CHURA, Auteur ; V. WARRIER, Auteur ; Bhismadev CHAKRABARTI, Auteur ; Edward T. BULLMORE, Auteur ; J. SUCKLING, Auteur ; D. FLORIS, Auteur ; Simon BARON-COHEN, Auteur . - 12 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 12 p. Mots-clés : Autism  Imaging genetics  Oxytocin receptor  Supramarginal gyrus  fMRI  the relevant national and institutional committees on human experimentation and  with the Declaration of Helsinki of 1975, as revised in 2008.Not applicable.The  authors declare that they have no competing interests.Springer Nature remains  neutral with regard to jurisdictional claims in published maps and institutional  affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism is a highly varied and heritable neurodevelopmental condition, and common variants explain approximately 50% of the genetic variance of autism. One of the genes implicated in autism is the oxytocin receptor (OXTR). The current study combined genetic and brain imaging (fMRI) data to examine the moderating effect of genotype on the association between diagnosis and brain activity in response to a test of cognitive empathy. Methods: Participants were adolescents (mean age = 14.7 +/- 1.7) who were genotyped for single nucleotide polymorphisms (SNPs) within the OXTR and underwent functional brain imaging while completing the adolescent version of the 'Reading the Mind in the Eyes' Test (Eyes Test). Results: Two (rs2254298, rs53576) of the five OXTR SNPs examined were significantly associated with brain activity during the Eyes Test, and three of the SNPs (rs2254298, rs53576, rs2268491) interacted with diagnostic status to predict brain activity. All of the effects localized to the right supramarginal gyrus (rSMG) and an overlap analysis revealed a large overlap of the effects. An exploratory analysis showed that activity within an anatomically defined rSMG and genotype can predict diagnostic status with reasonable accuracy. Conclusions: This is one of the first studies to investigate OXTR and brain function in autism. The findings suggest a neurogenetic mechanism by which OXTR-dependent activity within the rSMG is related to the aetiology of autism. En ligne : https://dx.doi.org/10.1186/s13229-019-0258-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

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