Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data / Olivia J. VEATCH in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data Type de document : texte imprimé Auteurs : Olivia J. VEATCH, Auteur ; Diego R. MAZZOTTI, Auteur ; Robert T. SCHULTZ, Auteur ; Ted ABEL, Auteur ; Jacob J. MICHAELSON, Auteur ; Edward S. BRODKIN, Auteur ; Birkan TUNC, Auteur ; Susan G. ASSOULINE, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Beth A. MALOW, Auteur ; James S. SUTCLIFFE, Auteur ; Allan I. PACK, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Autism Spectrum Disorder/complications/genetics  Biological Phenomena  Child  Exome/genetics  Humans  Sleep Wake Disorders/complications/genetics  Exome Sequencing  Autism spectrum disorders  Genetic risk scores  Pleiotropy  Sleep duration  Systems biology Index. décimale : PER Périodiques Résumé : BACKGROUND: Numerous genes are implicated in autism spectrum disorder (ASD). ASD encompasses a wide-range and severity of symptoms and co-occurring conditions; however, the details of how genetic variation contributes to phenotypic differences are unclear. This creates a challenge for translating genetic evidence into clinically useful knowledge. Sleep disturbances are particularly prevalent co-occurring conditions in ASD, and genetics may inform treatment. Identifying convergent mechanisms with evidence for dysfunction that connect ASD and sleep biology could help identify better treatments for sleep disturbances in these individuals. METHODS: To identify mechanisms that influence risk for ASD and co-occurring sleep disturbances, we analyzed whole exome sequence data from individuals in the Simons Simplex Collection (n = 2380). We predicted protein damaging variants (PDVs) in genes currently implicated in either ASD or sleep duration in typically developing children. We predicted a network of ASD-related proteins with direct evidence for interaction with sleep duration-related proteins encoded by genes with PDVs. Overrepresentation analyses of Gene Ontology-defined biological processes were conducted on the resulting gene set. We calculated the likelihood of dysfunction in the top overrepresented biological process. We then tested if scores reflecting genetic dysfunction in the process were associated with parent-reported sleep duration. RESULTS: There were 29 genes with PDVs in the ASD dataset where variation was reported in the literature to be associated with both ASD and sleep duration. A network of 108 proteins encoded by ASD and sleep duration candidate genes with PDVs was identified. The mechanism overrepresented in PDV-containing genes that encode proteins in the interaction network with the most evidence for dysfunction was cerebral cortex development (GO:0,021,987). Scores reflecting dysfunction in this process were associated with sleep durations; the largest effects were observed in adolescents (p = 4.65 × 10(-3)). CONCLUSIONS: Our bioinformatic-driven approach detected a biological process enriched for genes encoding a protein-protein interaction network linking ASD gene products with sleep duration gene products where accumulation of potentially damaging variants in individuals with ASD was associated with sleep duration as reported by the parents. Specifically, genetic dysfunction impacting development of the cerebral cortex may affect sleep by disrupting sleep homeostasis which is evidenced to be regulated by this brain region. Future functional assessments and objective measurements of sleep in adolescents with ASD could provide the basis for more informed treatment of sleep problems in these individuals. En ligne : https://dx.doi.org/10.1186/s11689-022-09448-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data [texte imprimé] / Olivia J. VEATCH, Auteur ; Diego R. MAZZOTTI, Auteur ; Robert T. SCHULTZ, Auteur ; Ted ABEL, Auteur ; Jacob J. MICHAELSON, Auteur ; Edward S. BRODKIN, Auteur ; Birkan TUNC, Auteur ; Susan G. ASSOULINE, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Beth A. MALOW, Auteur ; James S. SUTCLIFFE, Auteur ; Allan I. PACK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Adolescent  Autism Spectrum Disorder/complications/genetics  Biological Phenomena  Child  Exome/genetics  Humans  Sleep Wake Disorders/complications/genetics  Exome Sequencing  Autism spectrum disorders  Genetic risk scores  Pleiotropy  Sleep duration  Systems biology Index. décimale : PER Périodiques Résumé : BACKGROUND: Numerous genes are implicated in autism spectrum disorder (ASD). ASD encompasses a wide-range and severity of symptoms and co-occurring conditions; however, the details of how genetic variation contributes to phenotypic differences are unclear. This creates a challenge for translating genetic evidence into clinically useful knowledge. Sleep disturbances are particularly prevalent co-occurring conditions in ASD, and genetics may inform treatment. Identifying convergent mechanisms with evidence for dysfunction that connect ASD and sleep biology could help identify better treatments for sleep disturbances in these individuals. METHODS: To identify mechanisms that influence risk for ASD and co-occurring sleep disturbances, we analyzed whole exome sequence data from individuals in the Simons Simplex Collection (n = 2380). We predicted protein damaging variants (PDVs) in genes currently implicated in either ASD or sleep duration in typically developing children. We predicted a network of ASD-related proteins with direct evidence for interaction with sleep duration-related proteins encoded by genes with PDVs. Overrepresentation analyses of Gene Ontology-defined biological processes were conducted on the resulting gene set. We calculated the likelihood of dysfunction in the top overrepresented biological process. We then tested if scores reflecting genetic dysfunction in the process were associated with parent-reported sleep duration. RESULTS: There were 29 genes with PDVs in the ASD dataset where variation was reported in the literature to be associated with both ASD and sleep duration. A network of 108 proteins encoded by ASD and sleep duration candidate genes with PDVs was identified. The mechanism overrepresented in PDV-containing genes that encode proteins in the interaction network with the most evidence for dysfunction was cerebral cortex development (GO:0,021,987). Scores reflecting dysfunction in this process were associated with sleep durations; the largest effects were observed in adolescents (p = 4.65 × 10(-3)). CONCLUSIONS: Our bioinformatic-driven approach detected a biological process enriched for genes encoding a protein-protein interaction network linking ASD gene products with sleep duration gene products where accumulation of potentially damaging variants in individuals with ASD was associated with sleep duration as reported by the parents. Specifically, genetic dysfunction impacting development of the cerebral cortex may affect sleep by disrupting sleep homeostasis which is evidenced to be regulated by this brain region. Future functional assessments and objective measurements of sleep in adolescents with ASD could provide the basis for more informed treatment of sleep problems in these individuals. En ligne : https://dx.doi.org/10.1186/s11689-022-09448-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Etiologic heterogeneity, pleiotropy, and polygenicity in behaviorally defined intellectual and developmental disabilities / Jessica B. GIRAULT in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Etiologic heterogeneity, pleiotropy, and polygenicity in behaviorally defined intellectual and developmental disabilities Type de document : texte imprimé Auteurs : Jessica B. GIRAULT, Auteur ; Olivia J. VEATCH, Auteur ; Hyejung WON, Auteur Langues : Anglais (eng) Mots-clés : Child  Humans  Developmental Disabilities  Intellectual Disability Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s11689-024-09526-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Etiologic heterogeneity, pleiotropy, and polygenicity in behaviorally defined intellectual and developmental disabilities [texte imprimé] / Jessica B. GIRAULT, Auteur ; Olivia J. VEATCH, Auteur ; Hyejung WON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Child  Humans  Developmental Disabilities  Intellectual Disability Index. décimale : PER Périodiques En ligne : https://dx.doi.org/10.1186/s11689-024-09526-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay / Olivia J. VEATCH in Journal of Autism and Developmental Disorders, 45-1 (January 2015)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 45-1 (January 2015) . - p.100-110 Titre : Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay Type de document : texte imprimé Auteurs : Olivia J. VEATCH, Auteur ; Julie S. PENDERGAST, Auteur ; Melissa J. ALLEN, Auteur ; Roberta M. LEU, Auteur ; Carl Hirschie JOHNSON, Auteur ; Sarah H. ELSEA, Auteur ; Beth A. MALOW, Auteur Article en page(s) : p.100-110 Langues : Anglais (eng) Mots-clés : Comorbidities  Genetic analyses  Phenotyping  Phenotypic subgroups  Biomarkers  Endophenotypes Index. décimale : PER Périodiques Résumé : Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with comorbid expression of sleep onset delay. We evaluated variation in two melatonin pathway genes, acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2). We observed higher frequencies than currently reported (p < 0.04) for variants evidenced to decrease ASMT expression and related to decreased CYP1A2 enzyme activity (p ≤ 0.0007). We detected a relationship between genotypes in ASMT and CYP1A2 (r2 = 0.63). Our results indicate that expression of sleep onset delay relates to melatonin pathway genes. En ligne : http://dx.doi.org/10.1007/s10803-014-2197-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=258 [article] Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay [texte imprimé] / Olivia J. VEATCH, Auteur ; Julie S. PENDERGAST, Auteur ; Melissa J. ALLEN, Auteur ; Roberta M. LEU, Auteur ; Carl Hirschie JOHNSON, Auteur ; Sarah H. ELSEA, Auteur ; Beth A. MALOW, Auteur . - p.100-110. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 45-1 (January 2015) . - p.100-110 Mots-clés : Comorbidities  Genetic analyses  Phenotyping  Phenotypic subgroups  Biomarkers  Endophenotypes Index. décimale : PER Périodiques Résumé : Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with comorbid expression of sleep onset delay. We evaluated variation in two melatonin pathway genes, acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2). We observed higher frequencies than currently reported (p < 0.04) for variants evidenced to decrease ASMT expression and related to decreased CYP1A2 enzyme activity (p ≤ 0.0007). We detected a relationship between genotypes in ASMT and CYP1A2 (r2 = 0.63). Our results indicate that expression of sleep onset delay relates to melatonin pathway genes. En ligne : http://dx.doi.org/10.1007/s10803-014-2197-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=258

A practical approach to identifying autistic adults within the electronic health record / Olivia J. VEATCH ; Xinnan NIU ; Kasey A. FITZPATRICK ; Donald HUCKS ; Angie MAXWELL-HORN ; Lea K. DAVIS in Autism Research, 16-1 (January 2023)  

Public ISBD [article]  inAutism Research > 16-1 (January 2023) . - p.52-65 Titre : A practical approach to identifying autistic adults within the electronic health record Type de document : texte imprimé Auteurs : Olivia J. VEATCH, Auteur ; Xinnan NIU, Auteur ; Kasey A. FITZPATRICK, Auteur ; Donald HUCKS, Auteur ; Angie MAXWELL-HORN, Auteur ; Lea K. DAVIS, Auteur Article en page(s) : p.52-65 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Abstract The electronic health record (EHR) provides valuable data for understanding physical and mental health conditions in autism. We developed an approach to identify charts of autistic young adults, retrieved from our institution's de-identified EHR database. Clinical notes within two cohorts were identified. Cohort 1 charts had at least one International Classification of Diseases (ICD-CM) autism code. Cohort 2 charts had only autism key terms without ICD-CM codes, and at least four notes per chart. A natural language processing tool parsed medical charts to identify key terms associated with autism diagnoses and mapped them to Unified Medical Language System Concept Unique Identifiers (CUIs). Average scores were calculated for each set of charts based on captured CUIs. Chart review determined whether patients met criteria for autism using a classification rubric. In Cohort 1, of 418 patients, 361 were confirmed to have autism by chart review. Sensitivity was 0.99 and specificity was 0.68 with positive predictive value (PPV) of 0.97. Specificity improved to 0.81 (sensitivity was 0.95; PPV was 0.98) when the number of notes was limited to four or more per chart. In Cohort 2, 48 of 136 patients were confirmed to have autism by chart review. Sensitivity was 0.95, specificity was 0.73, and PPV was 0.70. Our approach, which included using key terms, identified autism charts with high sensitivity, even in the absence of ICD-CM codes. Relying on ICD-CM codes alone may result in inclusion of false positive cases and exclusion of true cases with autism. En ligne : https://doi.org/10.1002/aur.2849 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=492 [article] A practical approach to identifying autistic adults within the electronic health record [texte imprimé] / Olivia J. VEATCH, Auteur ; Xinnan NIU, Auteur ; Kasey A. FITZPATRICK, Auteur ; Donald HUCKS, Auteur ; Angie MAXWELL-HORN, Auteur ; Lea K. DAVIS, Auteur . - p.52-65. Langues : Anglais (eng) in Autism Research > 16-1 (January 2023) . - p.52-65 Index. décimale : PER Périodiques Résumé : Abstract The electronic health record (EHR) provides valuable data for understanding physical and mental health conditions in autism. We developed an approach to identify charts of autistic young adults, retrieved from our institution's de-identified EHR database. Clinical notes within two cohorts were identified. Cohort 1 charts had at least one International Classification of Diseases (ICD-CM) autism code. Cohort 2 charts had only autism key terms without ICD-CM codes, and at least four notes per chart. A natural language processing tool parsed medical charts to identify key terms associated with autism diagnoses and mapped them to Unified Medical Language System Concept Unique Identifiers (CUIs). Average scores were calculated for each set of charts based on captured CUIs. Chart review determined whether patients met criteria for autism using a classification rubric. In Cohort 1, of 418 patients, 361 were confirmed to have autism by chart review. Sensitivity was 0.99 and specificity was 0.68 with positive predictive value (PPV) of 0.97. Specificity improved to 0.81 (sensitivity was 0.95; PPV was 0.98) when the number of notes was limited to four or more per chart. In Cohort 2, 48 of 136 patients were confirmed to have autism by chart review. Sensitivity was 0.95, specificity was 0.73, and PPV was 0.70. Our approach, which included using key terms, identified autism charts with high sensitivity, even in the absence of ICD-CM codes. Relying on ICD-CM codes alone may result in inclusion of false positive cases and exclusion of true cases with autism. En ligne : https://doi.org/10.1002/aur.2849 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=492

Shorter sleep duration is associated with social impairment and comorbidities in ASD / Olivia J. VEATCH in Autism Research, 10-7 (July 2017)  

Public ISBD [article]  inAutism Research > 10-7 (July 2017) . - p.1221-1238 Titre : Shorter sleep duration is associated with social impairment and comorbidities in ASD Type de document : texte imprimé Auteurs : Olivia J. VEATCH, Auteur ; James S. SUTCLIFFE, Auteur ; Zachary WARREN, Auteur ; Brendan T. KEENAN, Auteur ; Melissa H. POTTER, Auteur ; Beth A. MALOW, Auteur Article en page(s) : p.1221-1238 Langues : Anglais (eng) Mots-clés : comorbid conditions  sleep (disorders)  subtypes (of ASD)  social cognition  neurology Index. décimale : PER Périodiques Résumé : Sleep disturbance, particularly insomnia, is common in children with autism spectrum disorders (ASD). Furthermore, disturbed sleep affects core symptoms and other related comorbidities. Understanding the causes and consequences of sleep disturbances in children with ASD is an important step toward mitigating these symptoms. To better understand the connection between sleep duration and ASD severity, we analyzed ASD-related symptoms using the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS), IQ scores, and parent reports of the average amount of time slept per night that were available in the medical histories of 2,714 children with ASD in the Simons Simplex Collection (SSC). The mean (SD) sleep duration was 555 minutes. Sleep duration and severity of core ASD symptoms were negatively correlated, and sleep duration and IQ scores were positively correlated. Regression results indicated that more severe social impairment, primarily a failure to develop peer relationships, is the core symptom most strongly associated with short sleep duration. Furthermore, increased severity for numerous maladaptive behaviors assessed on the Child Behavior Checklist, as well as reports of attention deficit disorder, depressive disorder, and obsessive compulsive disorder were associated with short sleep duration. Severity scores for social/communication impairment and restricted and repetitive behaviors (RRB) were increased, and IQ scores were decreased, for children reported to sleep ≤420 minutes per night (lower 5th percentile) compared to children sleeping ≥660 minutes (upper 95th percentile). Our results indicate that reduced amounts of sleep are related to more severe symptoms in children with ASD. En ligne : http://dx.doi.org/10.1002/aur.1765 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=309 [article] Shorter sleep duration is associated with social impairment and comorbidities in ASD [texte imprimé] / Olivia J. VEATCH, Auteur ; James S. SUTCLIFFE, Auteur ; Zachary WARREN, Auteur ; Brendan T. KEENAN, Auteur ; Melissa H. POTTER, Auteur ; Beth A. MALOW, Auteur . - p.1221-1238. Langues : Anglais (eng) in Autism Research > 10-7 (July 2017) . - p.1221-1238 Mots-clés : comorbid conditions  sleep (disorders)  subtypes (of ASD)  social cognition  neurology Index. décimale : PER Périodiques Résumé : Sleep disturbance, particularly insomnia, is common in children with autism spectrum disorders (ASD). Furthermore, disturbed sleep affects core symptoms and other related comorbidities. Understanding the causes and consequences of sleep disturbances in children with ASD is an important step toward mitigating these symptoms. To better understand the connection between sleep duration and ASD severity, we analyzed ASD-related symptoms using the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS), IQ scores, and parent reports of the average amount of time slept per night that were available in the medical histories of 2,714 children with ASD in the Simons Simplex Collection (SSC). The mean (SD) sleep duration was 555 minutes. Sleep duration and severity of core ASD symptoms were negatively correlated, and sleep duration and IQ scores were positively correlated. Regression results indicated that more severe social impairment, primarily a failure to develop peer relationships, is the core symptom most strongly associated with short sleep duration. Furthermore, increased severity for numerous maladaptive behaviors assessed on the Child Behavior Checklist, as well as reports of attention deficit disorder, depressive disorder, and obsessive compulsive disorder were associated with short sleep duration. Severity scores for social/communication impairment and restricted and repetitive behaviors (RRB) were increased, and IQ scores were decreased, for children reported to sleep ≤420 minutes per night (lower 5th percentile) compared to children sleeping ≥660 minutes (upper 95th percentile). Our results indicate that reduced amounts of sleep are related to more severe symptoms in children with ASD. En ligne : http://dx.doi.org/10.1002/aur.1765 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=309

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