Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism / R. CHEN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 14p. Titre : Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Type de document : Texte imprimé et/ou numérique Auteurs : R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*genetics/metabolism  Endophenotypes/blood  Exome  Female  Forkhead Transcription Factors/*genetics  Genetic Predisposition to Disease  Humans  Jumonji Domain-Containing Histone Demethylases/*genetics  Male  *Mutation  Nuclear Proteins/*genetics  Repressor Proteins/*genetics  Sequence Analysis, DNA/methods  Serotonin/*blood  Signal Transduction  Ubiquitin-Specific Proteases/*genetics  *5-ht  *Autism  *Autism spectrum disorder  *Compound heterozygotes  *De novo mutation  *Endophenotype  *Group-wise transmission/disequilibrium test  *Hyperserotonemia  *Rare variants  *Serotonin  *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism [Texte imprimé et/ou numérique] / R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur . - 14p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 14p. Mots-clés : Autism Spectrum Disorder/*genetics/metabolism  Endophenotypes/blood  Exome  Female  Forkhead Transcription Factors/*genetics  Genetic Predisposition to Disease  Humans  Jumonji Domain-Containing Histone Demethylases/*genetics  Male  *Mutation  Nuclear Proteins/*genetics  Repressor Proteins/*genetics  Sequence Analysis, DNA/methods  Serotonin/*blood  Signal Transduction  Ubiquitin-Specific Proteases/*genetics  *5-ht  *Autism  *Autism spectrum disorder  *Compound heterozygotes  *De novo mutation  *Endophenotype  *Group-wise transmission/disequilibrium test  *Hyperserotonemia  *Rare variants  *Serotonin  *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Novel copy number variants in children with autism and additional developmental anomalies / L. K. DAVIS in Journal of Neurodevelopmental Disorders, 1-4 (December 2009)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 1-4 (December 2009) . - p.292-301 Titre : Novel copy number variants in children with autism and additional developmental anomalies Type de document : Texte imprimé et/ou numérique Auteurs : L. K. DAVIS, Auteur ; K. J. MEYER, Auteur ; D. S. RUDD, Auteur ; A. L. LIBRANT, Auteur ; E. A. EPPING, Auteur ; V. C. SHEFFIELD, Auteur ; T. H. WASSINK, Auteur Article en page(s) : p.292-301 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip(R) (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone. En ligne : http://dx.doi.org/10.1007/s11689-009-9013-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=342 [article] Novel copy number variants in children with autism and additional developmental anomalies [Texte imprimé et/ou numérique] / L. K. DAVIS, Auteur ; K. J. MEYER, Auteur ; D. S. RUDD, Auteur ; A. L. LIBRANT, Auteur ; E. A. EPPING, Auteur ; V. C. SHEFFIELD, Auteur ; T. H. WASSINK, Auteur . - p.292-301. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 1-4 (December 2009) . - p.292-301 Index. décimale : PER Périodiques Résumé : Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip(R) (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone. En ligne : http://dx.doi.org/10.1007/s11689-009-9013-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=342

Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome / T. H. WASSINK in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.6 Titre : Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : T. H. WASSINK, Auteur ; Heather C. HAZLETT, Auteur ; L. K. DAVIS, Auteur ; A. L. REISS, Auteur ; J. PIVEN, Auteur Article en page(s) : p.6 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS. METHODS: Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles. RESULTS: MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10. CONCLUSIONS: The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS. En ligne : http://dx.doi.org/10.1186/1866-1955-6-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome [Texte imprimé et/ou numérique] / T. H. WASSINK, Auteur ; Heather C. HAZLETT, Auteur ; L. K. DAVIS, Auteur ; A. L. REISS, Auteur ; J. PIVEN, Auteur . - p.6. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.6 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS. METHODS: Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles. RESULTS: MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10. CONCLUSIONS: The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS. En ligne : http://dx.doi.org/10.1186/1866-1955-6-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

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