Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 / Susan E. MALONEY in Autism Research, 11-1 (January 2018)  

Public ISBD [article]  inAutism Research > 11-1 (January 2018) . - p.44-58 Titre : Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 Type de document : texte imprimé Auteurs : Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.44-58 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss‐of‐function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal‐separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole‐brain serotonin was observed in Nf1+/– mice, but whole‐brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD‐relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)‐relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333 [article] Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 [texte imprimé] / Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.44-58. Langues : Anglais (eng) in Autism Research > 11-1 (January 2018) . - p.44-58 Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss‐of‐function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal‐separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole‐brain serotonin was observed in Nf1+/– mice, but whole‐brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD‐relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)‐relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333

Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task / K. R. NYGAARD in Autism Research, 12-8 (August 2019)  

Public ISBD [article]  inAutism Research > 12-8 (August 2019) . - p.1171-1183 Titre : Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task Type de document : texte imprimé Auteurs : K. R. NYGAARD, Auteur ; S. E. MALONEY, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.1171-1183 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  mice  social behavior  social preference index  statistics  three-chambered social approach task Index. décimale : PER Périodiques Résumé : The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon existing assays to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD-relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within-group comparisons only, and then interpret a difference in significance levels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs: Erroneous Within-group Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach could produce misleading inferences. Our review of Social Approach studies of high-confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often does not correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models. Autism Res 2019, 12: 1171-1183. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret these data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies. En ligne : http://dx.doi.org/10.1002/aur.2154 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=405 [article] Erroneous inference based on a lack of preference within one group: Autism, mice, and the social approach task [texte imprimé] / K. R. NYGAARD, Auteur ; S. E. MALONEY, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.1171-1183. Langues : Anglais (eng) in Autism Research > 12-8 (August 2019) . - p.1171-1183 Mots-clés : autism spectrum disorder  mice  social behavior  social preference index  statistics  three-chambered social approach task Index. décimale : PER Périodiques Résumé : The Social Approach Task is commonly used to identify sociability deficits when modeling liability factors for autism spectrum disorder (ASD) in mice. It was developed to expand upon existing assays to examine distinct aspects of social behavior in rodents and has become a standard component of mouse ASD-relevant phenotyping pipelines. However, there is variability in the statistical analysis and interpretation of results from this task. A common analytical approach is to conduct within-group comparisons only, and then interpret a difference in significance levels as if it were a group difference, without any direct comparison. As an efficient shorthand, we named this approach EWOCs: Erroneous Within-group Only Comparisons. Here, we examined the prevalence of EWOCs and used simulations to test whether this approach could produce misleading inferences. Our review of Social Approach studies of high-confidence ASD genes revealed 45% of papers sampled used only this analytical approach. Through simulations, we then demonstrate how a lack of significant difference within one group often does not correspond to a significant difference between groups, and show this erroneous interpretation increases the rate of false positives up to 25%. Finally, we define a simple solution: use an index, like a social preference score, with direct statistical comparisons between groups to identify significant differences. We also provide power calculations to guide sample size in future studies. Overall, elimination of EWOCs and adoption of direct comparisons should result in more accurate, reliable, and reproducible data interpretations from the Social Approach Task across ASD liability models. Autism Res 2019, 12: 1171-1183. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Social Approach Task is widely used to assess social behavior in mice and is frequently used in studies modeling autism. However, reviewing published studies showed nearly half do not use correct comparisons to interpret these data. Using simulated and original data, we argue the correct statistical approach is a direct comparison of scores between groups. This simple solution should reduce false positives and improve consistency of results across studies. En ligne : http://dx.doi.org/10.1002/aur.2154 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=405

Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders / Rebecca L. OUWENGA in Molecular Autism, (March 2015)  

Public ISBD [article]  inMolecular Autism > (March 2015) . - p.1-7 Titre : Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders Type de document : texte imprimé Auteurs : Rebecca L. OUWENGA, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.1-7 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Many studies have demonstrated a robust statistical overlap between genes whose transcripts are reported as Fragile X Mental Retardation Protein (Fmrp)-binding targets and genes implicated in various psychiatric disorders, including autism. However, it is not clear how to interpret this overlap as the Fmrp protein itself is not considered to be central to all instances of these conditions. En ligne : http://dx.doi.org/10.1186/s13229-015-0008-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders [texte imprimé] / Rebecca L. OUWENGA, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.1-7. Langues : Anglais (eng) in Molecular Autism > (March 2015) . - p.1-7 Index. décimale : PER Périodiques Résumé : Many studies have demonstrated a robust statistical overlap between genes whose transcripts are reported as Fragile X Mental Retardation Protein (Fmrp)-binding targets and genes implicated in various psychiatric disorders, including autism. However, it is not clear how to interpret this overlap as the Fmrp protein itself is not considered to be central to all instances of these conditions. En ligne : http://dx.doi.org/10.1186/s13229-015-0008-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association / Han YUAN in Autism Research, 7-2 (April 2014)  

Public ISBD [article]  inAutism Research > 7-2 (April 2014) . - p.245-253 Titre : Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association Type de document : texte imprimé Auteurs : Han YUAN, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.245-253 Mots-clés : maternal genotype effect  autism  GWAS  AGRE  SSC Index. décimale : PER Périodiques Résumé : Like most psychiatric disorders, autism spectrum disorders have both a genetic and an environmental component. While previous studies have clearly demonstrated the contribution of in utero (prenatal) environment on autism risk, most of them focused on transient environmental factors. Based on a recent sibling study, we hypothesized that environmental factors could also come from the maternal genome, which would result in persistent effects across siblings. In this study, the possibility of maternal genotype effects was examined by looking for common variants (single-nucleotide polymorphisms or SNPs) in the maternal genome associated with increased risk of autism in children. A case/control genome-wide association study was performed using mothers of probands as cases, and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange and Illumina Genotype Control Database were used as our discovery cohort (n = 1616). The same analysis was then replicated on Simon Simplex Collection and Study of Addiction: Genetics and Environment datasets (n = 2732). We did not identify any SNP that reached genome-wide significance (P  10−8), and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect. En ligne : http://dx.doi.org/10.1002/aur.1363 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230 [article] Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association [texte imprimé] / Han YUAN, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.245-253. in Autism Research > 7-2 (April 2014) . - p.245-253 Mots-clés : maternal genotype effect  autism  GWAS  AGRE  SSC Index. décimale : PER Périodiques Résumé : Like most psychiatric disorders, autism spectrum disorders have both a genetic and an environmental component. While previous studies have clearly demonstrated the contribution of in utero (prenatal) environment on autism risk, most of them focused on transient environmental factors. Based on a recent sibling study, we hypothesized that environmental factors could also come from the maternal genome, which would result in persistent effects across siblings. In this study, the possibility of maternal genotype effects was examined by looking for common variants (single-nucleotide polymorphisms or SNPs) in the maternal genome associated with increased risk of autism in children. A case/control genome-wide association study was performed using mothers of probands as cases, and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange and Illumina Genotype Control Database were used as our discovery cohort (n = 1616). The same analysis was then replicated on Simon Simplex Collection and Study of Addiction: Genetics and Environment datasets (n = 2732). We did not identify any SNP that reached genome-wide significance (P  10−8), and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect. En ligne : http://dx.doi.org/10.1002/aur.1363 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus / Jake GOCKLEY in Molecular Autism, (May 2015)  

Public ISBD [article]  inMolecular Autism > (May 2015) . - p.1-10 Titre : The female protective effect in autism spectrum disorder is not mediated by a single genetic locus Type de document : texte imprimé Auteurs : Jake GOCKLEY, Auteur ; A. Jeremy WILLSEY, Auteur ; Shan DONG, Auteur ; Joseph D. DOUGHERTY, Auteur ; John N. CONSTANTINO, Auteur ; Stephan J. SANDERS, Auteur Article en page(s) : p.1-10 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. En ligne : http://dx.doi.org/10.1186/s13229-015-0014-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] The female protective effect in autism spectrum disorder is not mediated by a single genetic locus [texte imprimé] / Jake GOCKLEY, Auteur ; A. Jeremy WILLSEY, Auteur ; Shan DONG, Auteur ; Joseph D. DOUGHERTY, Auteur ; John N. CONSTANTINO, Auteur ; Stephan J. SANDERS, Auteur . - p.1-10. Langues : Anglais (eng) in Molecular Autism > (May 2015) . - p.1-10 Index. décimale : PER Périodiques Résumé : A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. En ligne : http://dx.doi.org/10.1186/s13229-015-0014-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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