An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males / Ren-Hua CHUNG in Molecular Autism, (November 2011)  

Public ISBD [article]  inMolecular Autism > (November 2011) . - 10 p. Titre : An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males Type de document : Texte imprimé et/ou numérique Auteurs : Ren-Hua CHUNG, Auteur ; Deqiong MA, Auteur ; Kai WANG, Auteur ; Dale HEDGES, Auteur ; James M. JAWORSKI, Auteur ; John R. GILBERT, Auteur ; Michael L. CUCCARO, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Gerard SCHELLENBERG, Auteur ; Hakon HAKONARSON, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur ; Eden R. MARTIN, Auteur Année de publication : 2011 Article en page(s) : 10 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.METHODS:We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.RESULTS:One SNP, rs17321050, in the transducin beta-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 x 10-6) and joint analysis (P value = 4.53 x 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 x 10-3) and passed the replication threshold in the validation data set (P = 2.56 x 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.CONCLUSIONS:TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk. En ligne : http://dx.doi.org/10.1186/2040-2392-2-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149 [article] An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males [Texte imprimé et/ou numérique] / Ren-Hua CHUNG, Auteur ; Deqiong MA, Auteur ; Kai WANG, Auteur ; Dale HEDGES, Auteur ; James M. JAWORSKI, Auteur ; John R. GILBERT, Auteur ; Michael L. CUCCARO, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Gerard SCHELLENBERG, Auteur ; Hakon HAKONARSON, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur ; Eden R. MARTIN, Auteur . - 2011 . - 10 p. Langues : Anglais (eng) in Molecular Autism > (November 2011) . - 10 p. Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.METHODS:We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.RESULTS:One SNP, rs17321050, in the transducin beta-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 x 10-6) and joint analysis (P value = 4.53 x 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 x 10-3) and passed the replication threshold in the validation data set (P = 2.56 x 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.CONCLUSIONS:TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk. En ligne : http://dx.doi.org/10.1186/2040-2392-2-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149

Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci / Dale HEDGES in Molecular Autism, (April 2012)  

Public ISBD [article]  inMolecular Autism > (April 2012) . - 27 p. Titre : Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci Type de document : Texte imprimé et/ou numérique Auteurs : Dale HEDGES, Auteur ; Kara L. HAMILTON, Auteur ; Stephanie J. SACHAROW, Auteur ; Laura NATIONS, Auteur ; Gary W. BEECHAM, Auteur ; Zhanna M. KOZHEKBAEVA, Auteur ; Brittany L. BUTLER, Auteur ; Holly N. CUKIER, Auteur ; Patrice L. WHITEHEAD, Auteur ; Deqiong MA, Auteur ; James M. JAWORSKI, Auteur ; Lubov NATHANSON, Auteur ; Joycelyn M. LEE, Auteur ; Stephen L. HAUSER, Auteur ; Jorge R. OKSENBERG, Auteur ; Michael L. CUCCARO, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur Année de publication : 2012 Article en page(s) : 27 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism. Methods As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. Results Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions. En ligne : http://dx.doi.org/10.1186/2040-2392-3-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=155 [article] Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci [Texte imprimé et/ou numérique] / Dale HEDGES, Auteur ; Kara L. HAMILTON, Auteur ; Stephanie J. SACHAROW, Auteur ; Laura NATIONS, Auteur ; Gary W. BEECHAM, Auteur ; Zhanna M. KOZHEKBAEVA, Auteur ; Brittany L. BUTLER, Auteur ; Holly N. CUKIER, Auteur ; Patrice L. WHITEHEAD, Auteur ; Deqiong MA, Auteur ; James M. JAWORSKI, Auteur ; Lubov NATHANSON, Auteur ; Joycelyn M. LEE, Auteur ; Stephen L. HAUSER, Auteur ; Jorge R. OKSENBERG, Auteur ; Michael L. CUCCARO, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur . - 2012 . - 27 p. Langues : Anglais (eng) in Molecular Autism > (April 2012) . - 27 p. Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism. Methods As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. Results Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions. En ligne : http://dx.doi.org/10.1186/2040-2392-3-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=155

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