Dépouillements

Common variation contributes to the genetic architecture of social communication traits / Beate ST POURCAIN in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : Common variation contributes to the genetic architecture of social communication traits Type de document : Texte imprimé et/ou numérique Auteurs : Beate ST POURCAIN, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; Wei ANG, Auteur ; Nicole WARRINGTON, Auteur ; Joseph GLESSNER, Auteur ; Kai WANG, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; Hakon HAKONARSON, Auteur ; Craig E. PENNELL, Auteur ; George SMITH, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery 1.0E-05) were replicated (0.009 P-replication [less than or equal to]0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-34 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Common variation contributes to the genetic architecture of social communication traits [Texte imprimé et/ou numérique] / Beate ST POURCAIN, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; Wei ANG, Auteur ; Nicole WARRINGTON, Auteur ; Joseph GLESSNER, Auteur ; Kai WANG, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; Hakon HAKONARSON, Auteur ; Craig E. PENNELL, Auteur ; George SMITH, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery 1.0E-05) were replicated (0.009 P-replication [less than or equal to]0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-34 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Test-retest reliability of the 'Reading the Mind in the Eyes' test: a one-year follow-up study / Enrique FERNANDEZ-ABASCAL in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : Test-retest reliability of the 'Reading the Mind in the Eyes' test: a one-year follow-up study Type de document : Texte imprimé et/ou numérique Auteurs : Enrique FERNANDEZ-ABASCAL, Auteur ; Rosario CABELLO, Auteur ; Pablo FERNANDEZ-BERROCAL, Auteur ; Simon BARON-COHEN, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The 'Reading the Mind in the Eyes' (Eyes) test is an advanced test of theory of mind. It is widely used to assess individual differences in social cognition and emotion recognition across different groups and cultures. The present study examined distributions of responses and scores on a Spanish version of the test in a non-clinical Spanish adult population, and assessed test-retest reliability over a 1-year interval. A total of 358 undergraduates of both sexes, age 18 to 65 years, completed the Spanish version of the test twice over an interval of 1 year. The Bland-Altman method was used to calculate test-retest reliability. Distributions of responses and scores were optimal. Test-retest reliability for total score on the Eyes test was .63 (P .01), based on the intraclass correlation coefficient. Test-retest reliability using the Bland-Altman method was fairly good. This is the first study providing evidence that the Eyes test is reliable and stable over a 1-year period, in a non-clinical sample of adults. En ligne : http://dx.doi.org/10.1186/2040-2392-4-33 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Test-retest reliability of the 'Reading the Mind in the Eyes' test: a one-year follow-up study [Texte imprimé et/ou numérique] / Enrique FERNANDEZ-ABASCAL, Auteur ; Rosario CABELLO, Auteur ; Pablo FERNANDEZ-BERROCAL, Auteur ; Simon BARON-COHEN, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : The 'Reading the Mind in the Eyes' (Eyes) test is an advanced test of theory of mind. It is widely used to assess individual differences in social cognition and emotion recognition across different groups and cultures. The present study examined distributions of responses and scores on a Spanish version of the test in a non-clinical Spanish adult population, and assessed test-retest reliability over a 1-year interval. A total of 358 undergraduates of both sexes, age 18 to 65 years, completed the Spanish version of the test twice over an interval of 1 year. The Bland-Altman method was used to calculate test-retest reliability. Distributions of responses and scores were optimal. Test-retest reliability for total score on the Eyes test was .63 (P .01), based on the intraclass correlation coefficient. Test-retest reliability using the Bland-Altman method was fairly good. This is the first study providing evidence that the Eyes test is reliable and stable over a 1-year period, in a non-clinical sample of adults. En ligne : http://dx.doi.org/10.1186/2040-2392-4-33 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Expression of non-protein-coding antisense RNAs in genomic regions related to autism spectrum disorders / Dmitry VELMESHEV in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : Expression of non-protein-coding antisense RNAs in genomic regions related to autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Dmitry VELMESHEV, Auteur ; Marco MAGISTRI, Auteur ; Mohammad FAGHIHI, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) manifest with neurodevelopmental phenotypes including communicative, social and behavioral impairments that affect as many as 1 in 88 children. The majority of autism cases have no known genetic cause, suggesting complex genetics of the disorder, but a few genes of large effect have been identified. In order to identify novel ASD genetic correlates, we investigated non-protein coding RNAs (ncRNAs) which are abundantly transcribed from the human genome, enriched in the brain, and have been implicated in neurodevelopmental disorders. Using an algorithm that we developed, we examined a publicly available transcriptomics database, AceView, to identify the natural antisense transcripts (NATs) that overlap with known autism-related genes. We validated the presence and differential expression of NATs in different brain regions of ASD and control brains using qRT-PCR. Additionally, we investigated the subcellular localization of these transcripts in a neuronal cell line using RNA-sequencing (RNA-seq). We found noncoding antisense RNA transcripts at approximately 40% of loci previously implicated in ASD. We confirmed the expression of 10 antisense RNAs in different postmortem human brain tissues. The expression of five antisense transcripts was found to be region-specific, suggesting a role for these ncRNAs in the development and function of specific brain regions. Some antisense RNAs overlapping suspected ASD genes exhibited concordant expression relative to their sense protein-coding genes, while other sense-antisense pairs demonstrate a discordant relationship. Interestingly, the antisense RNA corresponding to the SYNGAP1 locus (SYNGAP1-AS) was found to be differentially expressed in brain regions of patients with ASD compared to control individuals. RNA-seq analysis of subcellular compartments from SH-SY5Y human neuroblastoma cells demonstrated that antisense RNAs to ASD candidate genes are predominantly expressed in the nucleoplasmic or chromatin compartments, implying their involvement in nuclear-associated processes. Our data suggests that NATs are abundantly expressed from ASD-related loci and provide evidence for their roles in target gene regulation, neurodevelopment and autism pathogenesis. This class of RNA should therefore be considered in functional studies aimed at understanding genetic risk factors for ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-32 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Expression of non-protein-coding antisense RNAs in genomic regions related to autism spectrum disorders [Texte imprimé et/ou numérique] / Dmitry VELMESHEV, Auteur ; Marco MAGISTRI, Auteur ; Mohammad FAGHIHI, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) manifest with neurodevelopmental phenotypes including communicative, social and behavioral impairments that affect as many as 1 in 88 children. The majority of autism cases have no known genetic cause, suggesting complex genetics of the disorder, but a few genes of large effect have been identified. In order to identify novel ASD genetic correlates, we investigated non-protein coding RNAs (ncRNAs) which are abundantly transcribed from the human genome, enriched in the brain, and have been implicated in neurodevelopmental disorders. Using an algorithm that we developed, we examined a publicly available transcriptomics database, AceView, to identify the natural antisense transcripts (NATs) that overlap with known autism-related genes. We validated the presence and differential expression of NATs in different brain regions of ASD and control brains using qRT-PCR. Additionally, we investigated the subcellular localization of these transcripts in a neuronal cell line using RNA-sequencing (RNA-seq). We found noncoding antisense RNA transcripts at approximately 40% of loci previously implicated in ASD. We confirmed the expression of 10 antisense RNAs in different postmortem human brain tissues. The expression of five antisense transcripts was found to be region-specific, suggesting a role for these ncRNAs in the development and function of specific brain regions. Some antisense RNAs overlapping suspected ASD genes exhibited concordant expression relative to their sense protein-coding genes, while other sense-antisense pairs demonstrate a discordant relationship. Interestingly, the antisense RNA corresponding to the SYNGAP1 locus (SYNGAP1-AS) was found to be differentially expressed in brain regions of patients with ASD compared to control individuals. RNA-seq analysis of subcellular compartments from SH-SY5Y human neuroblastoma cells demonstrated that antisense RNAs to ASD candidate genes are predominantly expressed in the nucleoplasmic or chromatin compartments, implying their involvement in nuclear-associated processes. Our data suggests that NATs are abundantly expressed from ASD-related loci and provide evidence for their roles in target gene regulation, neurodevelopment and autism pathogenesis. This class of RNA should therefore be considered in functional studies aimed at understanding genetic risk factors for ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-4-32 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

A potentiated startle study of uncertainty and contextual anxiety in adolescents diagnosed with autism spectrum disorder / Paul D. CHAMBERLAIN in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : A potentiated startle study of uncertainty and contextual anxiety in adolescents diagnosed with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Paul D. CHAMBERLAIN, Auteur ; Jacqui RODGERS, Auteur ; Michael J. CROWLEY, Auteur ; Sarah WHITE, Auteur ; Mark FREESTON, Auteur ; Mikle SOUTH, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Beyond the core symptoms of autism spectrum disorder (ASD), associated symptoms of anxiety can cause substantial impairment for individuals affected by ASD and those who care for them. We utilized a potentiated startle paradigm with a puff of air to the neck as the unconditioned stimulus in order to investigate differences between response to cued fear and contextual anxiety among cognitively able adolescents diagnosed with ASD and an age- and IQ-matched typically developing group. In a threat-modulated startle paradigm, response patterns to neutral, predictable, and unpredictable conditions were comparable across typically developing and ASD youth in terms of startle response magnitude and latency. However, the ASD group showed significantly greater absolute startle responsivity at baseline and throughout the experiment, suggesting possibly enhanced general sensitivity to threatening contexts. The ASD group, but not the control group, demonstrated moderate to strong negative correlations between psychophysiological response to unpredictable threats (uncertainty) and questionnaire measures of generalized anxiety, intolerance of uncertainty, and repetitive behavior. Our data suggest enhanced general reactivity among the ASD group, possibly reflecting greater sensitivity to the threatening context of the startle paradigm. Associations with the response to uncertainty may help explain shared neurobehavioral mechanisms in ASD and anxiety. This task can provide useful targets for future neuroimaging and genetics studies as well as specific avenues for intervention. We emphasize the importance of further basic and clinical research into links among these important constructs. En ligne : http://dx.doi.org/10.1186/2040-2392-4-31 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] A potentiated startle study of uncertainty and contextual anxiety in adolescents diagnosed with autism spectrum disorder [Texte imprimé et/ou numérique] / Paul D. CHAMBERLAIN, Auteur ; Jacqui RODGERS, Auteur ; Michael J. CROWLEY, Auteur ; Sarah WHITE, Auteur ; Mark FREESTON, Auteur ; Mikle SOUTH, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : Beyond the core symptoms of autism spectrum disorder (ASD), associated symptoms of anxiety can cause substantial impairment for individuals affected by ASD and those who care for them. We utilized a potentiated startle paradigm with a puff of air to the neck as the unconditioned stimulus in order to investigate differences between response to cued fear and contextual anxiety among cognitively able adolescents diagnosed with ASD and an age- and IQ-matched typically developing group. In a threat-modulated startle paradigm, response patterns to neutral, predictable, and unpredictable conditions were comparable across typically developing and ASD youth in terms of startle response magnitude and latency. However, the ASD group showed significantly greater absolute startle responsivity at baseline and throughout the experiment, suggesting possibly enhanced general sensitivity to threatening contexts. The ASD group, but not the control group, demonstrated moderate to strong negative correlations between psychophysiological response to unpredictable threats (uncertainty) and questionnaire measures of generalized anxiety, intolerance of uncertainty, and repetitive behavior. Our data suggest enhanced general reactivity among the ASD group, possibly reflecting greater sensitivity to the threatening context of the startle paradigm. Associations with the response to uncertainty may help explain shared neurobehavioral mechanisms in ASD and anxiety. This task can provide useful targets for future neuroimaging and genetics studies as well as specific avenues for intervention. We emphasize the importance of further basic and clinical research into links among these important constructs. En ligne : http://dx.doi.org/10.1186/2040-2392-4-31 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders / Boryana STAMOVA in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Boryana STAMOVA, Auteur ; Yingfang TIAN, Auteur ; Christine W. NORDAHL, Auteur ; Mark SHEN, Auteur ; Sally J ROGERS, Auteur ; David G. AMARAL, Auteur ; Frank SHARP, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. RNA from blood was processed on whole genome exon arrays for 2-4-year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_LTCV versus ASD_NTCV. These differences were significant at P 0.05 after false discovery rate corrections for multiple comparisons (FDR 5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling. The only pathways significant after multiple comparison corrections (FDR 0.05) were the Nrf2-mediated reactive oxygen species (ROS) oxidative response (superoxide dismutase 2, catalase, peroxiredoxin 1, PIK3C3, DNAJC17, microsomal glutathione S-transferase 3) and superoxide radical degradation (SOD2, CAT). These data support differences in alternative splicing of mRNA in blood of ASD subjects compared to TD controls that differ related to head size. The findings are preliminary, need to be replicated in independent cohorts, and predicted alternative splicing differences need to be confirmed using direct analytical methods. En ligne : http://dx.doi.org/10.1186/2040-2392-4-30 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders [Texte imprimé et/ou numérique] / Boryana STAMOVA, Auteur ; Yingfang TIAN, Auteur ; Christine W. NORDAHL, Auteur ; Mark SHEN, Auteur ; Sally J ROGERS, Auteur ; David G. AMARAL, Auteur ; Frank SHARP, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. RNA from blood was processed on whole genome exon arrays for 2-4-year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_LTCV versus ASD_NTCV. These differences were significant at P 0.05 after false discovery rate corrections for multiple comparisons (FDR 5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling. The only pathways significant after multiple comparison corrections (FDR 0.05) were the Nrf2-mediated reactive oxygen species (ROS) oxidative response (superoxide dismutase 2, catalase, peroxiredoxin 1, PIK3C3, DNAJC17, microsomal glutathione S-transferase 3) and superoxide radical degradation (SOD2, CAT). These data support differences in alternative splicing of mRNA in blood of ASD subjects compared to TD controls that differ related to head size. The findings are preliminary, need to be replicated in independent cohorts, and predicted alternative splicing differences need to be confirmed using direct analytical methods. En ligne : http://dx.doi.org/10.1186/2040-2392-4-30 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227