3 recherche sur le mot-clé 'molecular'

Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism / Thomas W FRAZIER in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 5p. Titre : Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism Type de document : Texte imprimé et/ou numérique Auteurs : Thomas W FRAZIER, Auteur ; Ritika JAINI, Auteur ; Robyn M. BUSCH, Auteur ; Matthew WOLF, Auteur ; Tammy SADLER, Auteur ; Patricia KLAAS, Auteur ; Antonio Y. HARDAN, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Chari ENG, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Behavior  Cognition  Molecular  Pten  Protein Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446. En ligne : http://dx.doi.org/10.1186/s13229-020-00406-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442 [article] Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism [Texte imprimé et/ou numérique] / Thomas W FRAZIER, Auteur ; Ritika JAINI, Auteur ; Robyn M. BUSCH, Auteur ; Matthew WOLF, Auteur ; Tammy SADLER, Auteur ; Patricia KLAAS, Auteur ; Antonio Y. HARDAN, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Chari ENG, Auteur . - 5p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 5p. Mots-clés : Autism spectrum disorder  Behavior  Cognition  Molecular  Pten  Protein Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446. En ligne : http://dx.doi.org/10.1186/s13229-020-00406-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442

Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood / Alexander NEUMANN in Journal of Child Psychology and Psychiatry, 63-6 (June 2022)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 63-6 (June 2022) . - p.636-645 Titre : Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood Type de document : Texte imprimé et/ou numérique Auteurs : Alexander NEUMANN, Auteur ; Alexia JOLICOEUR-MARTINEAU, Auteur ; Eszter SZEKELY, Auteur ; Hannah M. SALLIS, Auteur ; Kieran O'DONNEL, Auteur ; Celia M. T. GREENWOOD, Auteur ; Robert LEVITAN, Auteur ; Michael J. MEANEY, Auteur ; Ashley WAZANA, Auteur ; Jonathan P. EVANS, Auteur ; Henning TIEMEIER, Auteur Article en page(s) : p.636-645 Langues : Anglais (eng) Mots-clés : Genetics  comorbidity  externalizing disorder  internalizing disorder  meta-analysis  molecular Index. décimale : PER Périodiques Résumé : BACKGROUND: Polygenic risk scores (PRSs) operationalize genetic propensity toward a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection, it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance. METHODS: We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9,247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands), and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-report and parental, teacher, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor. RESULTS: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology. CONCLUSIONS: The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of nonspecificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders. En ligne : http://dx.doi.org/10.1111/jcpp.13501 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=475 [article] Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood [Texte imprimé et/ou numérique] / Alexander NEUMANN, Auteur ; Alexia JOLICOEUR-MARTINEAU, Auteur ; Eszter SZEKELY, Auteur ; Hannah M. SALLIS, Auteur ; Kieran O'DONNEL, Auteur ; Celia M. T. GREENWOOD, Auteur ; Robert LEVITAN, Auteur ; Michael J. MEANEY, Auteur ; Ashley WAZANA, Auteur ; Jonathan P. EVANS, Auteur ; Henning TIEMEIER, Auteur . - p.636-645. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 63-6 (June 2022) . - p.636-645 Mots-clés : Genetics  comorbidity  externalizing disorder  internalizing disorder  meta-analysis  molecular Index. décimale : PER Périodiques Résumé : BACKGROUND: Polygenic risk scores (PRSs) operationalize genetic propensity toward a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection, it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance. METHODS: We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9,247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands), and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-report and parental, teacher, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor. RESULTS: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology. CONCLUSIONS: The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of nonspecificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders. En ligne : http://dx.doi.org/10.1111/jcpp.13501 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=475

Violence exposure in an urban city: A GxE interaction with aggressive and impulsive behaviors / R. J. MUSCI in Journal of Child Psychology and Psychiatry, 60-1 (January 2019)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 60-1 (January 2019) . - p.72-81 Titre : Violence exposure in an urban city: A GxE interaction with aggressive and impulsive behaviors Type de document : Texte imprimé et/ou numérique Auteurs : R. J. MUSCI, Auteur ; Amie F. BETTENCOURT, Auteur ; D. SISTO, Auteur ; B. MAHER, Auteur ; K. MASYN, Auteur ; N. S. IALONGO, Auteur Article en page(s) : p.72-81 Langues : Anglais (eng) Mots-clés : Aggression  genetics  molecular  violence Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous research has demonstrated a reciprocal relationship between community violence exposure and disruptive behavior problems among youth. No study to date, however, has explored the potential interaction between violence exposure in early adolescence and genetics. METHODS: We explore the gene x environment interaction's impact on teacher-rated aggressive and impulsive behaviors. Violence exposure during the middle school years was assessed using self-report. Genetic data collection occurred in emerging adulthood. A polygenic score was created using findings from a conduct disorder symptomatology genome-wide association study. RESULTS: Three longitudinal classes of teacher reported aggressive and impulsive behavior were identified. We found a significant relationship between violence exposure and class membership. There was a significant GxE interaction, such that those with below average levels of the polygenic score and who were exposed to violence were more likely to be in the moderately high aggressive and impulsive class as compared to the no to low class. CONCLUSIONS: These findings highlight the influence of genetic risk together with violence exposure on adolescent problem behavior. Although youth may have little control over the environments in which they live, interventions can and should focus on helping all youth. En ligne : http://dx.doi.org/10.1111/jcpp.12966 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=374 [article] Violence exposure in an urban city: A GxE interaction with aggressive and impulsive behaviors [Texte imprimé et/ou numérique] / R. J. MUSCI, Auteur ; Amie F. BETTENCOURT, Auteur ; D. SISTO, Auteur ; B. MAHER, Auteur ; K. MASYN, Auteur ; N. S. IALONGO, Auteur . - p.72-81. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 60-1 (January 2019) . - p.72-81 Mots-clés : Aggression  genetics  molecular  violence Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous research has demonstrated a reciprocal relationship between community violence exposure and disruptive behavior problems among youth. No study to date, however, has explored the potential interaction between violence exposure in early adolescence and genetics. METHODS: We explore the gene x environment interaction's impact on teacher-rated aggressive and impulsive behaviors. Violence exposure during the middle school years was assessed using self-report. Genetic data collection occurred in emerging adulthood. A polygenic score was created using findings from a conduct disorder symptomatology genome-wide association study. RESULTS: Three longitudinal classes of teacher reported aggressive and impulsive behavior were identified. We found a significant relationship between violence exposure and class membership. There was a significant GxE interaction, such that those with below average levels of the polygenic score and who were exposed to violence were more likely to be in the moderately high aggressive and impulsive class as compared to the no to low class. CONCLUSIONS: These findings highlight the influence of genetic risk together with violence exposure on adolescent problem behavior. Although youth may have little control over the environments in which they live, interventions can and should focus on helping all youth. En ligne : http://dx.doi.org/10.1111/jcpp.12966 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=374