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

Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk / Jerome CARAYOL in Molecular Autism, (February 2010)  

Public ISBD [article]  inMolecular Autism > (February 2010) . - 11 p. Titre : Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk Type de document : Texte imprimé et/ou numérique Auteurs : Jerome CARAYOL, Auteur ; Geraldine DAWSON, Auteur ; Gerard SCHELLENBERG, Auteur ; Frederic TORES, Auteur ; Jörg HAGER, Auteur ; Andreas ZIEGLER, Auteur Année de publication : 2010 Article en page(s) : 11 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Autism is a complex disorder characterized by deficits involving communication, social interaction, and repetitive and restrictive patterns of behavior. Twin studies have shown that autism is strongly heritable, suggesting a strong genetic component. In other disease states with a complex etiology, such as type 2 diabetes, cancer and cardiovascular disease, combined analysis of multiple genetic variants in a genetic score has helped to identify individuals at high risk of disease. Genetic scores are designed to test for association of genetic markers with disease. Method The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population. Results In both samples, odds ratios (ORs) increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49). The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59). Conclusions These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk. En ligne : http://dx.doi.org/10.1186/2040-2392-1-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102 [article] Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk [Texte imprimé et/ou numérique] / Jerome CARAYOL, Auteur ; Geraldine DAWSON, Auteur ; Gerard SCHELLENBERG, Auteur ; Frederic TORES, Auteur ; Jörg HAGER, Auteur ; Andreas ZIEGLER, Auteur . - 2010 . - 11 p. Langues : Anglais (eng) in Molecular Autism > (February 2010) . - 11 p. Index. décimale : PER Périodiques Résumé : Background Autism is a complex disorder characterized by deficits involving communication, social interaction, and repetitive and restrictive patterns of behavior. Twin studies have shown that autism is strongly heritable, suggesting a strong genetic component. In other disease states with a complex etiology, such as type 2 diabetes, cancer and cardiovascular disease, combined analysis of multiple genetic variants in a genetic score has helped to identify individuals at high risk of disease. Genetic scores are designed to test for association of genetic markers with disease. Method The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population. Results In both samples, odds ratios (ORs) increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49). The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59). Conclusions These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk. En ligne : http://dx.doi.org/10.1186/2040-2392-1-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102

Autism risk assessment in siblings of affected children using sex-specific genetic scores / Jerome CARAYOL in Molecular Autism, (October 2011)  

Public ISBD [article]  inMolecular Autism > (October 2011) . - 8 p. Titre : Autism risk assessment in siblings of affected children using sex-specific genetic scores Type de document : Texte imprimé et/ou numérique Auteurs : Jerome CARAYOL, Auteur ; Gerard SCHELLENBERG, Auteur ; Beth DOMBROSKI, Auteur ; Emmanuelle GENIN, Auteur ; Francis ROUSSEAU, Auteur ; Geraldine DAWSON, Auteur Année de publication : 2011 Article en page(s) : 8 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system.METHODS:SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism.RESULTS:We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 x 10-6 and 1.9 x 10-5, respectively).CONCLUSIONS:Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism. En ligne : http://dx.doi.org/10.1186/2040-2392-2-17 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149 [article] Autism risk assessment in siblings of affected children using sex-specific genetic scores [Texte imprimé et/ou numérique] / Jerome CARAYOL, Auteur ; Gerard SCHELLENBERG, Auteur ; Beth DOMBROSKI, Auteur ; Emmanuelle GENIN, Auteur ; Francis ROUSSEAU, Auteur ; Geraldine DAWSON, Auteur . - 2011 . - 8 p. Langues : Anglais (eng) in Molecular Autism > (October 2011) . - 8 p. Index. décimale : PER Périodiques Résumé : BACKGROUND:The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system.METHODS:SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism.RESULTS:We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 x 10-6 and 1.9 x 10-5, respectively).CONCLUSIONS:Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism. En ligne : http://dx.doi.org/10.1186/2040-2392-2-17 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149

Quantitative Assessment of Autism Symptom-related Traits in Probands and Parents: Broader Phenotype Autism Symptom Scale / Geraldine DAWSON in Journal of Autism and Developmental Disorders, 37-3 (March 2007)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 37-3 (March 2007) . - p.523-536 Titre : Quantitative Assessment of Autism Symptom-related Traits in Probands and Parents: Broader Phenotype Autism Symptom Scale Type de document : Texte imprimé et/ou numérique Auteurs : Geraldine DAWSON, Auteur ; Annette ESTES, Auteur ; Jeffrey MUNSON, Auteur ; Gerard SCHELLENBERG, Auteur ; Raphael BERNIER, Auteur ; Robert ABBOTT, Auteur Année de publication : 2007 Article en page(s) : p.523-536 Langues : Anglais (eng) Mots-clés : Broader-phenotype Genetics Quantitative-traits Index. décimale : PER Périodiques Résumé : Autism susceptibility genes likely have effects on continuously distributed autism-related traits, yet few measures of such traits exist. The Broader Phenotype Autism Symptom Scale (BPASS), developed for use with affected children and family members, measures social motivation, social expressiveness, conversational skills, and flexibility. Based on 201 multiplex families, psychometric data on the BPASS are reported. Adequate inter-rater reliability and internal consistency were found. Parents had lower BPASS scores than affected children, after controlling for IQ. Parents and affected children showed overlapping distributions suggesting the BPASS captured variability in traits across groups. BPASS scores were not correlated with ethnicity or parent education; however, some domains were correlated with IQ. The BPASS holds promise as a quantitative phenotypic assessment for genetic studies. En ligne : http://dx.doi.org/10.1007/s10803-006-0182-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=656 [article] Quantitative Assessment of Autism Symptom-related Traits in Probands and Parents: Broader Phenotype Autism Symptom Scale [Texte imprimé et/ou numérique] / Geraldine DAWSON, Auteur ; Annette ESTES, Auteur ; Jeffrey MUNSON, Auteur ; Gerard SCHELLENBERG, Auteur ; Raphael BERNIER, Auteur ; Robert ABBOTT, Auteur . - 2007 . - p.523-536. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 37-3 (March 2007) . - p.523-536 Mots-clés : Broader-phenotype Genetics Quantitative-traits Index. décimale : PER Périodiques Résumé : Autism susceptibility genes likely have effects on continuously distributed autism-related traits, yet few measures of such traits exist. The Broader Phenotype Autism Symptom Scale (BPASS), developed for use with affected children and family members, measures social motivation, social expressiveness, conversational skills, and flexibility. Based on 201 multiplex families, psychometric data on the BPASS are reported. Adequate inter-rater reliability and internal consistency were found. Parents had lower BPASS scores than affected children, after controlling for IQ. Parents and affected children showed overlapping distributions suggesting the BPASS captured variability in traits across groups. BPASS scores were not correlated with ethnicity or parent education; however, some domains were correlated with IQ. The BPASS holds promise as a quantitative phenotypic assessment for genetic studies. En ligne : http://dx.doi.org/10.1007/s10803-006-0182-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=656

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