A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism / John P. HUSSMAN in Molecular Autism, (January 2011)  

Public ISBD [article]  inMolecular Autism > (January 2011) . - 16 p. Titre : A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism Type de document : Texte imprimé et/ou numérique Auteurs : John P. HUSSMAN, Auteur ; Ren-Hua CHUNG, Auteur ; Anthony J. GRISWOLD, Auteur ; James M. JAWORSKI, Auteur ; Daria SALYAKINA, Auteur ; Deqiong MA, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Jeffery M. VANCE, Auteur ; Eden R. MARTIN, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur Année de publication : 2011 Article en page(s) : 16 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. Methods GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. Results Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. Conclusions As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism. En ligne : http://dx.doi.org/10.1186/2040-2392-2-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=121 [article] A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism [Texte imprimé et/ou numérique] / John P. HUSSMAN, Auteur ; Ren-Hua CHUNG, Auteur ; Anthony J. GRISWOLD, Auteur ; James M. JAWORSKI, Auteur ; Daria SALYAKINA, Auteur ; Deqiong MA, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Jeffery M. VANCE, Auteur ; Eden R. MARTIN, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur . - 2011 . - 16 p. Langues : Anglais (eng) in Molecular Autism > (January 2011) . - 16 p. Index. décimale : PER Périodiques Résumé : Background Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. Methods GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. Results Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. Conclusions As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism. En ligne : http://dx.doi.org/10.1186/2040-2392-2-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=121

A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis / Anthony J. GRISWOLD in Autism Research, 4-3 (June 2011)  

Public ISBD [article]  inAutism Research > 4-3 (June 2011) . - p.221-227 Titre : A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis Type de document : Texte imprimé et/ou numérique Auteurs : Anthony J. GRISWOLD, Auteur ; Deqiong MA, Auteur ; Stephanie J. SACHAROW, Auteur ; Joycelyn L. ROBINSON, Auteur ; James M. JAWORSKI, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Helle LYBAEK, Auteur ; Nina OYEN, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur Année de publication : 2011 Article en page(s) : p.221-227 Langues : Anglais (eng) Mots-clés : genetics  copy number variation  molecular genetics Index. décimale : PER Périodiques Résumé : Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5–7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm. We identified and validated a de novo 1.5 Mb microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes, including spectrin beta (SPTB), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G member 3 (PLEKHG3), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 (CHURC1), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk. En ligne : http://dx.doi.org/10.1002/aur.186 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=127 [article] A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis [Texte imprimé et/ou numérique] / Anthony J. GRISWOLD, Auteur ; Deqiong MA, Auteur ; Stephanie J. SACHAROW, Auteur ; Joycelyn L. ROBINSON, Auteur ; James M. JAWORSKI, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Helle LYBAEK, Auteur ; Nina OYEN, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur . - 2011 . - p.221-227. Langues : Anglais (eng) in Autism Research > 4-3 (June 2011) . - p.221-227 Mots-clés : genetics  copy number variation  molecular genetics Index. décimale : PER Périodiques Résumé : Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5–7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm. We identified and validated a de novo 1.5 Mb microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes, including spectrin beta (SPTB), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G member 3 (PLEKHG3), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 (CHURC1), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk. En ligne : http://dx.doi.org/10.1002/aur.186 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=127

Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants / Anthony J. GRISWOLD in Molecular Autism, (July 2015)  

Public ISBD [article]  inMolecular Autism > (July 2015) . - p.1-11 Titre : Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants Type de document : Texte imprimé et/ou numérique Auteurs : Anthony J. GRISWOLD, Auteur ; Nicole D. DUEKER, Auteur ; Derek BOOVEN, Auteur ; Joseph A. RANTUS, Auteur ; James M. JAWORSKI, Auteur ; Susan H. SLIFER, Auteur ; Michael A. SCHMIDT, Auteur ; William HULME, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Michael L. CUCCARO, Auteur ; Eden R. MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; John P. HUSSMAN, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur Article en page(s) : p.1-11 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. En ligne : http://dx.doi.org/10.1186/s13229-015-0034-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants [Texte imprimé et/ou numérique] / Anthony J. GRISWOLD, Auteur ; Nicole D. DUEKER, Auteur ; Derek BOOVEN, Auteur ; Joseph A. RANTUS, Auteur ; James M. JAWORSKI, Auteur ; Susan H. SLIFER, Auteur ; Michael A. SCHMIDT, Auteur ; William HULME, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Michael L. CUCCARO, Auteur ; Eden R. MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; John P. HUSSMAN, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur . - p.1-11. Langues : Anglais (eng) in Molecular Autism > (July 2015) . - p.1-11 Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. En ligne : http://dx.doi.org/10.1186/s13229-015-0034-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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