Brain functional connectivity correlates of autism diagnosis and familial liability in 24-month-olds / John R. Jr PRUETT in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Brain functional connectivity correlates of autism diagnosis and familial liability in 24-month-olds Type de document : texte imprimé Auteurs : John R. Jr PRUETT, Auteur ; Alexandre A. TODOROV, Auteur ; Zoë W. HAWKS, Auteur ; Muhamed TALOVIĆ, Auteur ; Tomoyuki NISHINO, Auteur ; Steven E. PETERSEN, Auteur ; Savannah DAVIS, Auteur ; Lyn STAHL, Auteur ; Kelly N. BOTTERON, Auteur ; John N. CONSTANTINO, Auteur ; Stephen R. DAGER, Auteur ; Jed T. ELISON, Auteur ; Annette M. ESTES, Auteur ; Alan C. EVANS, Auteur ; Guido GERIG, Auteur ; Jessica B. GIRAULT, Auteur ; Heather HAZLETT, Auteur ; Leigh MACINTYRE, Auteur ; Natasha MARRUS, Auteur ; Robert C. MCKINSTRY, Auteur ; Juhi PANDEY, Auteur ; Robert T. SCHULTZ, Auteur ; William D. SHANNON, Auteur ; Mark D. SHEN, Auteur ; Abraham Z. SNYDER, Auteur ; Martin STYNER, Auteur ; Jason J. WOLFF, Auteur ; Lonnie ZWAIGENBAUM, Auteur ; Joseph PIVEN, Auteur ; THE IBIS NETWORK, Auteur Langues : Anglais (eng) Mots-clés : Humans  Male  Female  Magnetic Resonance Imaging  Autism Spectrum Disorder/physiopathology/diagnostic imaging  Child, Preschool  Brain/physiopathology/diagnostic imaging  Support Vector Machine  Connectome  Nerve Net/physiopathology/diagnostic imaging  Infant  Siblings  Default mode network  Familial  Functional connectivity  MRI  reviewed and approved by the internal review boards of Washington University  School of Medicine, IRB IDs 201103140 and 201301110, the University of  Washington, IRB IDs 12317 and STUDY00012991, The Children’s Hospital of  Philadelphia, IRB ID 07-005689, and the University of North Carolina at Chapel  Hill, IRB ID 05-2293. Informed consent was signed by all study participants.  Competing interests: Dr. Robert McKinstry serves on the advisory board of Nous  Imaging, Inc. and receives funding for meals and travel from Siemens Healthineers  and Philips Healthcare. Abraham Z. Snyder is a consultant for Sora Neuroscience,  LLC. All other authors report no financial relationships with commercial  interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: fcMRI correlates of autism spectrum disorder (ASD) diagnosis and familial liability were studied in 24-month-olds at high (older affected sibling) and low familial likelihood for ASD. METHODS: fcMRI comparisons of high-familial-likelihood (HL) ASD-positive (HLP, N = 23) and ASD-negative (HLN, N = 91), and low-likelihood ASD-negative (LLN, N = 27) 24-month-olds from the Infant Brain Imaging Study (IBIS) Network were conducted, employing object oriented data analysis (OODA), support vector machine (SVM) classification, and network-level fcMRI enrichment analyses. RESULTS: OODA (alpha = 0.0167, 3 comparisons) revealed differences in HLP and LLN fcMRI matrices (p = 0.012), but none for HLP versus HLN (p = 0.047) nor HLN versus LLN (p = 0.225). SVM distinguished HLP from HLN (accuracy = 99%, PPV = 96%, NPV = 100%), based on connectivity involving many networks. SVM accurately classified (non-training) LLN subjects with 100% accuracy. Enrichment analyses identified a cross-group fcMRI difference in the posterior cingulate default mode network 1 (pcDMN1)- temporal default mode network (tDMN) pair (p = 0.0070). Functional connectivity for implicated connections in these networks was consistently lower in HLP and HLN than in LLN (p = 0.0461 and 0.0004). HLP did not differ from HLN (p = 0.2254). Secondary testing showed HL children with low ASD behaviors still differed from LLN (p = 0.0036). CONCLUSIONS: 24-month-old high-familial-likelihood infants show reduced intra-DMN connectivity, a potential neural finding related to familial liability, while widely distributed functional connections correlate with ASD diagnosis. En ligne : https://dx.doi.org/10.1186/s11689-025-09621-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Brain functional connectivity correlates of autism diagnosis and familial liability in 24-month-olds [texte imprimé] / John R. Jr PRUETT, Auteur ; Alexandre A. TODOROV, Auteur ; Zoë W. HAWKS, Auteur ; Muhamed TALOVIĆ, Auteur ; Tomoyuki NISHINO, Auteur ; Steven E. PETERSEN, Auteur ; Savannah DAVIS, Auteur ; Lyn STAHL, Auteur ; Kelly N. BOTTERON, Auteur ; John N. CONSTANTINO, Auteur ; Stephen R. DAGER, Auteur ; Jed T. ELISON, Auteur ; Annette M. ESTES, Auteur ; Alan C. EVANS, Auteur ; Guido GERIG, Auteur ; Jessica B. GIRAULT, Auteur ; Heather HAZLETT, Auteur ; Leigh MACINTYRE, Auteur ; Natasha MARRUS, Auteur ; Robert C. MCKINSTRY, Auteur ; Juhi PANDEY, Auteur ; Robert T. SCHULTZ, Auteur ; William D. SHANNON, Auteur ; Mark D. SHEN, Auteur ; Abraham Z. SNYDER, Auteur ; Martin STYNER, Auteur ; Jason J. WOLFF, Auteur ; Lonnie ZWAIGENBAUM, Auteur ; Joseph PIVEN, Auteur ; THE IBIS NETWORK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Humans  Male  Female  Magnetic Resonance Imaging  Autism Spectrum Disorder/physiopathology/diagnostic imaging  Child, Preschool  Brain/physiopathology/diagnostic imaging  Support Vector Machine  Connectome  Nerve Net/physiopathology/diagnostic imaging  Infant  Siblings  Default mode network  Familial  Functional connectivity  MRI  reviewed and approved by the internal review boards of Washington University  School of Medicine, IRB IDs 201103140 and 201301110, the University of  Washington, IRB IDs 12317 and STUDY00012991, The Children’s Hospital of  Philadelphia, IRB ID 07-005689, and the University of North Carolina at Chapel  Hill, IRB ID 05-2293. Informed consent was signed by all study participants.  Competing interests: Dr. Robert McKinstry serves on the advisory board of Nous  Imaging, Inc. and receives funding for meals and travel from Siemens Healthineers  and Philips Healthcare. Abraham Z. Snyder is a consultant for Sora Neuroscience,  LLC. All other authors report no financial relationships with commercial  interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: fcMRI correlates of autism spectrum disorder (ASD) diagnosis and familial liability were studied in 24-month-olds at high (older affected sibling) and low familial likelihood for ASD. METHODS: fcMRI comparisons of high-familial-likelihood (HL) ASD-positive (HLP, N = 23) and ASD-negative (HLN, N = 91), and low-likelihood ASD-negative (LLN, N = 27) 24-month-olds from the Infant Brain Imaging Study (IBIS) Network were conducted, employing object oriented data analysis (OODA), support vector machine (SVM) classification, and network-level fcMRI enrichment analyses. RESULTS: OODA (alpha = 0.0167, 3 comparisons) revealed differences in HLP and LLN fcMRI matrices (p = 0.012), but none for HLP versus HLN (p = 0.047) nor HLN versus LLN (p = 0.225). SVM distinguished HLP from HLN (accuracy = 99%, PPV = 96%, NPV = 100%), based on connectivity involving many networks. SVM accurately classified (non-training) LLN subjects with 100% accuracy. Enrichment analyses identified a cross-group fcMRI difference in the posterior cingulate default mode network 1 (pcDMN1)- temporal default mode network (tDMN) pair (p = 0.0070). Functional connectivity for implicated connections in these networks was consistently lower in HLP and HLN than in LLN (p = 0.0461 and 0.0004). HLP did not differ from HLN (p = 0.2254). Secondary testing showed HL children with low ASD behaviors still differed from LLN (p = 0.0036). CONCLUSIONS: 24-month-old high-familial-likelihood infants show reduced intra-DMN connectivity, a potential neural finding related to familial liability, while widely distributed functional connections correlate with ASD diagnosis. En ligne : https://dx.doi.org/10.1186/s11689-025-09621-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Brain volumes, cognitive, and adaptive skills in school-age children with Down syndrome / Rebecca GRZADZINSKI in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Brain volumes, cognitive, and adaptive skills in school-age children with Down syndrome Type de document : texte imprimé Auteurs : Rebecca GRZADZINSKI, Auteur ; Kattia MATA, Auteur ; Ambika S. BHATT, Auteur ; Alapika JATKAR, Auteur ; Dea GARIC, Auteur ; Mark D. SHEN, Auteur ; Jessica B. GIRAULT, Auteur ; Tanya ST JOHN, Auteur ; Juhi PANDEY, Auteur ; Lonnie ZWAIGENBAUM, Auteur ; Annette ESTES, Auteur ; Audrey M. SHEN, Auteur ; Stephen DAGER, Auteur ; Robert SCHULTZ, Auteur ; Kelly BOTTERON, Auteur ; Natasha MARRUS, Auteur ; Martin STYNER, Auteur ; Alan EVANS, Auteur ; Sun Hyung KIM, Auteur ; Robert MCKINSTRY, Auteur ; Guido GERIG, Auteur ; Joseph PIVEN, Auteur ; Heather HAZLETT, Auteur ; IBIS NETWORK, Auteur Langues : Anglais (eng) Mots-clés : Humans  Down Syndrome/diagnostic imaging/physiopathology/pathology  Male  Female  Child  Magnetic Resonance Imaging  Adaptation, Psychological/physiology  Cognition/physiology  Brain/diagnostic imaging/pathology/physiopathology  Autism Spectrum Disorder/diagnostic imaging/physiopathology/pathology  Organ Size  Cerebellum/diagnostic imaging/pathology/physiopathology  Adaptive  Autism spectrum disorder  Brain volumes  Cognitive  Cortical volumes  Down syndrome  Intellectual disability  Mri  Neurobehavioral/behavioral profiles  Neurodevelopmental disorder  Neuroimaging  School-age children  in this work was approved by the local Institutional Review Board. Consent for  publication: All authors have reviewed the manuscript and approved it for  publication. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Down syndrome (DS) is the most common congenital neurodevelopmental disorder, present in about 1 in every 700 live births. Despite its prevalence, literature exploring the neurobiology underlying DS and how this neurobiology is related to behavior is limited. This study fills this gap by examining cortical volumes and behavioral correlates in school-age children with DS. METHODS: School-age children (mean = 9.7 years ± 1.1) underwent comprehensive assessments, including cognitive and adaptive assessments, as well as an MRI scan without the use of sedation. Children with DS (n = 35) were compared to available samples of typically developing (TD; n = 80) and ASD children (n = 29). ANOVAs were conducted to compare groups on cognitive and adaptive assessments. ANCOVAs (covarying for age, sex, and total cerebral volume; TCV) compared cortical brain volumes between groups. Correlations between behavioral metrics and cortical and cerebellar volumes (separately for gray (GM) and white matter (WM)) were conducted separately by group. RESULTS: As expected, children with DS had significantly lower cognitive skills compared to ASD and TD children. Daily Living adaptive skills were comparable between ASD children and children with DS, and both groups scored lower than TD children. Children with DS exhibited a smaller TCV compared to ASD and TD children. Additionally, when controlling for TCV, age, and sex, children with DS had significantly smaller total GM and tissue volumes. Cerebellum volumes were significantly correlated with Daily Living adaptive behaviors in the DS group only. CONCLUSIONS: Despite children with DS exhibiting lower cognitive skills and smaller brain volume overall than children with ASD, their deficits in Socialization and Daily Living adaptive skills are comparable. Differences in lobar volumes (e.g., Right Frontal GM/WM, Left Frontal WM, and Left and Right Temporal WM) were observed above and beyond overall differences in total volume. The correlation between cerebellum volumes and Daily Living adaptive behaviors in the DS group provides a novel area to explore in future research. En ligne : https://dx.doi.org/10.1186/s11689-024-09581-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Brain volumes, cognitive, and adaptive skills in school-age children with Down syndrome [texte imprimé] / Rebecca GRZADZINSKI, Auteur ; Kattia MATA, Auteur ; Ambika S. BHATT, Auteur ; Alapika JATKAR, Auteur ; Dea GARIC, Auteur ; Mark D. SHEN, Auteur ; Jessica B. GIRAULT, Auteur ; Tanya ST JOHN, Auteur ; Juhi PANDEY, Auteur ; Lonnie ZWAIGENBAUM, Auteur ; Annette ESTES, Auteur ; Audrey M. SHEN, Auteur ; Stephen DAGER, Auteur ; Robert SCHULTZ, Auteur ; Kelly BOTTERON, Auteur ; Natasha MARRUS, Auteur ; Martin STYNER, Auteur ; Alan EVANS, Auteur ; Sun Hyung KIM, Auteur ; Robert MCKINSTRY, Auteur ; Guido GERIG, Auteur ; Joseph PIVEN, Auteur ; Heather HAZLETT, Auteur ; IBIS NETWORK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Down Syndrome/diagnostic imaging/physiopathology/pathology  Male  Female  Child  Magnetic Resonance Imaging  Adaptation, Psychological/physiology  Cognition/physiology  Brain/diagnostic imaging/pathology/physiopathology  Autism Spectrum Disorder/diagnostic imaging/physiopathology/pathology  Organ Size  Cerebellum/diagnostic imaging/pathology/physiopathology  Adaptive  Autism spectrum disorder  Brain volumes  Cognitive  Cortical volumes  Down syndrome  Intellectual disability  Mri  Neurobehavioral/behavioral profiles  Neurodevelopmental disorder  Neuroimaging  School-age children  in this work was approved by the local Institutional Review Board. Consent for  publication: All authors have reviewed the manuscript and approved it for  publication. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Down syndrome (DS) is the most common congenital neurodevelopmental disorder, present in about 1 in every 700 live births. Despite its prevalence, literature exploring the neurobiology underlying DS and how this neurobiology is related to behavior is limited. This study fills this gap by examining cortical volumes and behavioral correlates in school-age children with DS. METHODS: School-age children (mean = 9.7 years ± 1.1) underwent comprehensive assessments, including cognitive and adaptive assessments, as well as an MRI scan without the use of sedation. Children with DS (n = 35) were compared to available samples of typically developing (TD; n = 80) and ASD children (n = 29). ANOVAs were conducted to compare groups on cognitive and adaptive assessments. ANCOVAs (covarying for age, sex, and total cerebral volume; TCV) compared cortical brain volumes between groups. Correlations between behavioral metrics and cortical and cerebellar volumes (separately for gray (GM) and white matter (WM)) were conducted separately by group. RESULTS: As expected, children with DS had significantly lower cognitive skills compared to ASD and TD children. Daily Living adaptive skills were comparable between ASD children and children with DS, and both groups scored lower than TD children. Children with DS exhibited a smaller TCV compared to ASD and TD children. Additionally, when controlling for TCV, age, and sex, children with DS had significantly smaller total GM and tissue volumes. Cerebellum volumes were significantly correlated with Daily Living adaptive behaviors in the DS group only. CONCLUSIONS: Despite children with DS exhibiting lower cognitive skills and smaller brain volume overall than children with ASD, their deficits in Socialization and Daily Living adaptive skills are comparable. Differences in lobar volumes (e.g., Right Frontal GM/WM, Left Frontal WM, and Left and Right Temporal WM) were observed above and beyond overall differences in total volume. The correlation between cerebellum volumes and Daily Living adaptive behaviors in the DS group provides a novel area to explore in future research. En ligne : https://dx.doi.org/10.1186/s11689-024-09581-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Cerebrospinal fluid and the early brain development of autism / Mark D. SHEN in Journal of Neurodevelopmental Disorders, 10-1 (December 2018)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 39 p. Titre : Cerebrospinal fluid and the early brain development of autism Type de document : texte imprimé Auteurs : Mark D. SHEN, Auteur Année de publication : 2018 Article en page(s) : 39 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Biomarkers  Brain development  Brain enlargement  Cerebrospinal fluid  Early risk signs  Extra-axial cerebrospinal fluid  Glymphatic system  Heterogeneity  Infancy  Lateral ventricles  Neural meningeal lymphatic system  Neuroinflammation  Stratification biomarker Index. décimale : PER Périodiques Résumé : BACKGROUND: There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory proteins involved in neurodegenerative diseases, such as amyloid-beta. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system. MAIN BODY: This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment. CONCLUSION: The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments. En ligne : http://dx.doi.org/10.1186/s11689-018-9256-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386 [article] Cerebrospinal fluid and the early brain development of autism [texte imprimé] / Mark D. SHEN, Auteur . - 2018 . - 39 p. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 39 p. Mots-clés : Autism spectrum disorder  Biomarkers  Brain development  Brain enlargement  Cerebrospinal fluid  Early risk signs  Extra-axial cerebrospinal fluid  Glymphatic system  Heterogeneity  Infancy  Lateral ventricles  Neural meningeal lymphatic system  Neuroinflammation  Stratification biomarker Index. décimale : PER Périodiques Résumé : BACKGROUND: There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory proteins involved in neurodegenerative diseases, such as amyloid-beta. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system. MAIN BODY: This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment. CONCLUSION: The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments. En ligne : http://dx.doi.org/10.1186/s11689-018-9256-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386

Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder / Michael YAO in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder Type de document : texte imprimé Auteurs : Michael YAO, Auteur ; Jason DANIELS, Auteur ; Luke GROSVENOR, Auteur ; Valerie MORRILL, Auteur ; Jason I. FEINBERG, Auteur ; Kelly M. BAKULSKI, Auteur ; Joseph PIVEN, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Craig NEWSCHAFFER, Auteur ; Kristen LYALL, Auteur ; Rebecca J. SCHMIDT, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Lisa A. CROEN, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur ; Heather VOLK, Auteur ; Kelly BENKE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Multifactorial Inheritance  Genetic Predisposition to Disease  Male  Female  Genotype  Polymorphism, Single Nucleotide  Autism spectrum disorder (ASD)  Information Loss  Polygenic scores (PGS) Index. décimale : PER Périodiques Résumé : BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. En ligne : https://dx.doi.org/10.1186/s11689-024-09571-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder [texte imprimé] / Michael YAO, Auteur ; Jason DANIELS, Auteur ; Luke GROSVENOR, Auteur ; Valerie MORRILL, Auteur ; Jason I. FEINBERG, Auteur ; Kelly M. BAKULSKI, Auteur ; Joseph PIVEN, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Craig NEWSCHAFFER, Auteur ; Kristen LYALL, Auteur ; Rebecca J. SCHMIDT, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Lisa A. CROEN, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur ; Heather VOLK, Auteur ; Kelly BENKE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Multifactorial Inheritance  Genetic Predisposition to Disease  Male  Female  Genotype  Polymorphism, Single Nucleotide  Autism spectrum disorder (ASD)  Information Loss  Polygenic scores (PGS) Index. décimale : PER Périodiques Résumé : BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. En ligne : https://dx.doi.org/10.1186/s11689-024-09571-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Comparative profiling of white matter development in the human and mouse brain reveals volumetric deficits and delayed myelination in Angelman syndrome / Ridthi K-R PATEL ; Tasmai VULLI ; Audrey L SMITH ; Martin A. STYNER ; Li-Ming HSU ; Sung-Ho LEE ; Yen-Yu Ian SHIH ; Heather C. HAZLETT ; Mark D. SHEN ; Alain C BURETTE ; Benjamin D. PHILPOT in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 54 Titre : Comparative profiling of white matter development in the human and mouse brain reveals volumetric deficits and delayed myelination in Angelman syndrome Type de document : texte imprimé Auteurs : Ridthi K-R PATEL, Auteur ; Tasmai VULLI, Auteur ; Audrey L SMITH, Auteur ; Martin A. STYNER, Auteur ; Li-Ming HSU, Auteur ; Sung-Ho LEE, Auteur ; Yen-Yu Ian SHIH, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Alain C BURETTE, Auteur ; Benjamin D. PHILPOT, Auteur Article en page(s) : 54 Langues : Anglais (eng) Mots-clés : Animals  *Angelman Syndrome/genetics/pathology/diagnostic imaging  *White Matter/diagnostic imaging/pathology  Humans  Female  Male  Child, Preschool  *Myelin Sheath/metabolism/pathology  Infant  Child  Mice  *Ubiquitin-Protein Ligases/genetics/metabolism  Magnetic Resonance Imaging  Brain/diagnostic imaging/pathology/metabolism  Disease Models, Animal  Organ Size  Mice, Knockout  Microcephaly  Myelin basic protein  Myelination  Ube3a  White matter  and treatment of animals followed institutional and NIH guidelines, and all  animal use protocols were reviewed and approved by the UNC Institutional Animal  Care and Use Committee. Parents of AS and NT individuals provided informed  consent, and the institutional review board approved the research protocol.  Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain's white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still poorly characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the possibility of underlying WM neuropathology by examining the progression of myelination in an AS mouse model. METHODS: We conducted magnetic resonance imaging (MRI) on children with AS (n = 32) and neurotypical controls (n = 99) aged 0.5-12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice (Ube3a(m-/p+); AS model), Ube3a paternal-null mice (Ube3a(m+/p-)), and wildtype controls (Ube3a(m+/p+)) using MRI, immunohistochemistry, western blotting, and electron microscopy. RESULTS: Our data revealed that AS individuals exhibit significant reductions in brain volume by ~ 1 year of age, and by 6-12 years of age WM is reduced by 26% and gray matter by 21%-approximately twice the reductions observed in the adult AS mouse model. Our AS mouse model saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal abnormalities in myelinated or unmyelinated axons. LIMITATIONS: It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS. CONCLUSIONS: This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show these deficits occur alongside the delayed onset of myelination, which results from the loss of neuronal (but not glial) UBE3A, though the causal relationship between these phenotypes remains to be determined. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments. En ligne : https://dx.doi.org/10.1186/s13229-024-00636-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Comparative profiling of white matter development in the human and mouse brain reveals volumetric deficits and delayed myelination in Angelman syndrome [texte imprimé] / Ridthi K-R PATEL, Auteur ; Tasmai VULLI, Auteur ; Audrey L SMITH, Auteur ; Martin A. STYNER, Auteur ; Li-Ming HSU, Auteur ; Sung-Ho LEE, Auteur ; Yen-Yu Ian SHIH, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Alain C BURETTE, Auteur ; Benjamin D. PHILPOT, Auteur . - 54. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 54 Mots-clés : Animals  *Angelman Syndrome/genetics/pathology/diagnostic imaging  *White Matter/diagnostic imaging/pathology  Humans  Female  Male  Child, Preschool  *Myelin Sheath/metabolism/pathology  Infant  Child  Mice  *Ubiquitin-Protein Ligases/genetics/metabolism  Magnetic Resonance Imaging  Brain/diagnostic imaging/pathology/metabolism  Disease Models, Animal  Organ Size  Mice, Knockout  Microcephaly  Myelin basic protein  Myelination  Ube3a  White matter  and treatment of animals followed institutional and NIH guidelines, and all  animal use protocols were reviewed and approved by the UNC Institutional Animal  Care and Use Committee. Parents of AS and NT individuals provided informed  consent, and the institutional review board approved the research protocol.  Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain's white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still poorly characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the possibility of underlying WM neuropathology by examining the progression of myelination in an AS mouse model. METHODS: We conducted magnetic resonance imaging (MRI) on children with AS (n = 32) and neurotypical controls (n = 99) aged 0.5-12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice (Ube3a(m-/p+); AS model), Ube3a paternal-null mice (Ube3a(m+/p-)), and wildtype controls (Ube3a(m+/p+)) using MRI, immunohistochemistry, western blotting, and electron microscopy. RESULTS: Our data revealed that AS individuals exhibit significant reductions in brain volume by ~ 1 year of age, and by 6-12 years of age WM is reduced by 26% and gray matter by 21%-approximately twice the reductions observed in the adult AS mouse model. Our AS mouse model saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal abnormalities in myelinated or unmyelinated axons. LIMITATIONS: It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS. CONCLUSIONS: This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show these deficits occur alongside the delayed onset of myelination, which results from the loss of neuronal (but not glial) UBE3A, though the causal relationship between these phenotypes remains to be determined. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments. En ligne : https://dx.doi.org/10.1186/s13229-024-00636-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

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