Dépouillements

Common genetic variants, acting additively, are a major source of risk for autism / Lambertus KLEI in Molecular Autism, (October 2012)  

Public ISBD [article]  inMolecular Autism > (October 2012) . - 13 p. Titre : Common genetic variants, acting additively, are a major source of risk for autism Type de document : Texte imprimé et/ou numérique Auteurs : Lambertus KLEI, Auteur ; Stephan J. SANDERS, Auteur ; Michael T. MURTHA, Auteur ; Vanessa HUS, Auteur ; Jennifer K. LOWE, Auteur ; A. J. WILLSEY, Auteur ; Daniel MORENO DE LUCA, Auteur ; Timothy W. YU, Auteur ; Eric FOMBONNE, Auteur ; Daniel H. GESCHWIND, Auteur ; Dorothy E. GRICE, Auteur ; David H. LEDBETTER, Auteur ; Catherine LORD, Auteur ; Shrikant M. MANE, Auteur ; Christa L. MARTIN, Auteur ; Donna M. MARTIN, Auteur ; Eric M. MORROW, Auteur ; Christopher A. WALSH, Auteur ; Nadine M. MELHEM, Auteur ; Pauline CHASTE, Auteur ; James S. SUTCLIFFE, Auteur ; Matthew W. STATE, Auteur ; Edwin H. Jr COOK, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur Année de publication : 2012 Article en page(s) : 13 p. Langues : Anglais (eng) Mots-clés : Narrow-sense heritability  Multiplex  Simplex  Quantitative genetics Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability. En ligne : http://dx.doi.org/10.1186/2040-2392-3-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] Common genetic variants, acting additively, are a major source of risk for autism [Texte imprimé et/ou numérique] / Lambertus KLEI, Auteur ; Stephan J. SANDERS, Auteur ; Michael T. MURTHA, Auteur ; Vanessa HUS, Auteur ; Jennifer K. LOWE, Auteur ; A. J. WILLSEY, Auteur ; Daniel MORENO DE LUCA, Auteur ; Timothy W. YU, Auteur ; Eric FOMBONNE, Auteur ; Daniel H. GESCHWIND, Auteur ; Dorothy E. GRICE, Auteur ; David H. LEDBETTER, Auteur ; Catherine LORD, Auteur ; Shrikant M. MANE, Auteur ; Christa L. MARTIN, Auteur ; Donna M. MARTIN, Auteur ; Eric M. MORROW, Auteur ; Christopher A. WALSH, Auteur ; Nadine M. MELHEM, Auteur ; Pauline CHASTE, Auteur ; James S. SUTCLIFFE, Auteur ; Matthew W. STATE, Auteur ; Edwin H. Jr COOK, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur . - 2012 . - 13 p. Langues : Anglais (eng) in Molecular Autism > (October 2012) . - 13 p. Mots-clés : Narrow-sense heritability  Multiplex  Simplex  Quantitative genetics Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability. En ligne : http://dx.doi.org/10.1186/2040-2392-3-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202

Vldlr overexpression causes hyperactivity in rats / Keiko IWATA in Molecular Autism, (October 2012)  

Public ISBD [article]  inMolecular Autism > (October 2012) . - 9 p. Titre : Vldlr overexpression causes hyperactivity in rats Type de document : Texte imprimé et/ou numérique Auteurs : Keiko IWATA, Auteur ; Nobuo IZUMO, Auteur ; Hideo MATSUZAKI, Auteur ; Takayuki MANABE, Auteur ; Yukiko ISHIBASHI, Auteur ; Yukio ICHITANI, Auteur ; Kazuo YAMADA, Auteur ; Ismail THANSEEM, Auteur ; Ayyappan ANITHA, Auteur ; Mahesh VASU, Auteur ; Chie SHIMMURA, Auteur ; Tomoyasu WAKUDA, Auteur ; Yosuke KAMENO, Auteur ; Taro TAKAHASHI, Auteur ; Yasuhide IWATA, Auteur ; Katsuaki SUZUKI, Auteur ; Kazuhiko NAKAMURA, Auteur ; Norio MORI, Auteur Année de publication : 2012 Article en page(s) : 9 p. Langues : Anglais (eng) Mots-clés : Hyperactivity  Neurodevelopmental disorder  Psychiatric disorder  Reelin  Transgenic rat  Vldlr Index. décimale : PER Périodiques Résumé : BACKGROUND:Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients.METHODS:We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.RESULTS:Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function.CONCLUSIONS:Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities. En ligne : http://dx.doi.org/10.1186/2040-2392-3-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] Vldlr overexpression causes hyperactivity in rats [Texte imprimé et/ou numérique] / Keiko IWATA, Auteur ; Nobuo IZUMO, Auteur ; Hideo MATSUZAKI, Auteur ; Takayuki MANABE, Auteur ; Yukiko ISHIBASHI, Auteur ; Yukio ICHITANI, Auteur ; Kazuo YAMADA, Auteur ; Ismail THANSEEM, Auteur ; Ayyappan ANITHA, Auteur ; Mahesh VASU, Auteur ; Chie SHIMMURA, Auteur ; Tomoyasu WAKUDA, Auteur ; Yosuke KAMENO, Auteur ; Taro TAKAHASHI, Auteur ; Yasuhide IWATA, Auteur ; Katsuaki SUZUKI, Auteur ; Kazuhiko NAKAMURA, Auteur ; Norio MORI, Auteur . - 2012 . - 9 p. Langues : Anglais (eng) in Molecular Autism > (October 2012) . - 9 p. Mots-clés : Hyperactivity  Neurodevelopmental disorder  Psychiatric disorder  Reelin  Transgenic rat  Vldlr Index. décimale : PER Périodiques Résumé : BACKGROUND:Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients.METHODS:We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.RESULTS:Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function.CONCLUSIONS:Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities. En ligne : http://dx.doi.org/10.1186/2040-2392-3-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders / Hans KALKMAN in Molecular Autism, (October 2012)  

Public ISBD [article]  inMolecular Autism > (October 2012) . - 12 p. Titre : A review of the evidence for the canonical Wnt pathway in autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Hans KALKMAN, Auteur Année de publication : 2012 Article en page(s) : 12 p. Langues : Anglais (eng) Mots-clés : WNT2  FZD9  BCL9  DOCK4  DISC1  ADAM10  Valproate  SSRI Index. décimale : PER Périodiques Résumé : Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity. En ligne : http://dx.doi.org/10.1186/2040-2392-3-10 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] A review of the evidence for the canonical Wnt pathway in autism spectrum disorders [Texte imprimé et/ou numérique] / Hans KALKMAN, Auteur . - 2012 . - 12 p. Langues : Anglais (eng) in Molecular Autism > (October 2012) . - 12 p. Mots-clés : WNT2  FZD9  BCL9  DOCK4  DISC1  ADAM10  Valproate  SSRI Index. décimale : PER Périodiques Résumé : Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity. En ligne : http://dx.doi.org/10.1186/2040-2392-3-10 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202