Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders / Dale CANNON in Molecular Autism, (February 2010)  

Public ISBD [article]  inMolecular Autism > (February 2010) . - 13 p. Titre : Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Dale CANNON, Auteur ; William M. MCMAHON, Auteur ; Hilary H. COON, Auteur ; Kristina ALLEN-BRADY, Auteur ; Reid ROBISON, Auteur ; Judith S. MILLER, Auteur ; Michele E. VILLALOBOS, Auteur ; Natalie K. WAHMHOFF, Auteur Année de publication : 2010 Article en page(s) : 13 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS) and 'repetitive sensory-motor actions' (RSMA) are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales. Methods A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees. Results Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled. Conclusions The finding that IS and RSMA are linked to different regions that only partially overlap regions previously identified with ASD as the phenotype supports the value of including multiple, narrowly defined phenotypes in ASD genetic research. Further, we replicated previous reports indicating that RSMA is more strongly associated than IS with measures of ASD severity. En ligne : http://dx.doi.org/10.1186/2040-2392-1-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102 [article] Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders [Texte imprimé et/ou numérique] / Dale CANNON, Auteur ; William M. MCMAHON, Auteur ; Hilary H. COON, Auteur ; Kristina ALLEN-BRADY, Auteur ; Reid ROBISON, Auteur ; Judith S. MILLER, Auteur ; Michele E. VILLALOBOS, Auteur ; Natalie K. WAHMHOFF, Auteur . - 2010 . - 13 p. Langues : Anglais (eng) in Molecular Autism > (February 2010) . - 13 p. Index. décimale : PER Périodiques Résumé : Background It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS) and 'repetitive sensory-motor actions' (RSMA) are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales. Methods A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees. Results Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled. Conclusions The finding that IS and RSMA are linked to different regions that only partially overlap regions previously identified with ASD as the phenotype supports the value of including multiple, narrowly defined phenotypes in ASD genetic research. Further, we replicated previous reports indicating that RSMA is more strongly associated than IS with measures of ASD severity. En ligne : http://dx.doi.org/10.1186/2040-2392-1-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102

Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees / Hilary H. COON in Molecular Autism, (April 2010)  

Public ISBD [article]  inMolecular Autism > (April 2010) . - 14 p. Titre : Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees Type de document : Texte imprimé et/ou numérique Auteurs : Hilary H. COON, Auteur ; William M. MCMAHON, Auteur ; Kristina ALLEN-BRADY, Auteur ; Dale CANNON, Auteur ; Reid ROBISON, Auteur ; Judith S. MILLER, Auteur ; Michele E. VILLALOBOS, Auteur ; Nicola J. CAMP, Auteur Année de publication : 2010 Article en page(s) : 14 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability. Methods We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees. Results When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19. Conclusions The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected. En ligne : http://dx.doi.org/10.1186/2040-2392-1-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102 [article] Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees [Texte imprimé et/ou numérique] / Hilary H. COON, Auteur ; William M. MCMAHON, Auteur ; Kristina ALLEN-BRADY, Auteur ; Dale CANNON, Auteur ; Reid ROBISON, Auteur ; Judith S. MILLER, Auteur ; Michele E. VILLALOBOS, Auteur ; Nicola J. CAMP, Auteur . - 2010 . - 14 p. Langues : Anglais (eng) in Molecular Autism > (April 2010) . - 14 p. Index. décimale : PER Périodiques Résumé : Background Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability. Methods We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees. Results When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19. Conclusions The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected. En ligne : http://dx.doi.org/10.1186/2040-2392-1-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102

No evidence for IL1RAPL1 involvement in selected high-risk autism pedigrees from the AGRE data set / Kristina ALLEN-BRADY in Autism Research, 4-4 (August 2011)  

Public ISBD [article]  inAutism Research > 4-4 (August 2011) . - p.293-296 Titre : No evidence for IL1RAPL1 involvement in selected high-risk autism pedigrees from the AGRE data set Type de document : Texte imprimé et/ou numérique Auteurs : Kristina ALLEN-BRADY, Auteur ; Guiqing CAI, Auteur ; Dale CANNON, Auteur ; Reid ROBISON, Auteur ; William M. MCMAHON, Auteur ; Hilary H. COON, Auteur ; Joseph D. BUXBAUM, Auteur Année de publication : 2011 Article en page(s) : p.293-296 Langues : Anglais (eng) Mots-clés : behavioral analysis of animal models  developmental neurobiology  sex differences  testosterone  androgen receptor Index. décimale : PER Périodiques Résumé : Finding predisposition genes for Autism Spectrum Disorder (ASD) has proven challenging, and new methods are needed to aid the process. Using pedigree structure as a strategy to identify ASD predisposition genes, we previously performed a genome-wide linkage scan of 86 selected families from the Autism Resource Exchange (AGRE) that appeared to inherit ASD in a dominant manner. We identified a suggestive linkage peak on chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene, a strong candidate gene for ASD. In this follow-up study, we sequenced the coding regions of the IL1RAPL1 gene in 14 male cases representing one case from each pedigree that showed at least nominal linkage evidence on per pedigree basis to the chromosome X region. We observed no deleterious mutations or deletions in the IL1RAPL1 gene in these 14 ASD cases. A SNP was identified in exon 2 in five cases and a variant of unknown significance was identified in intron 6 in a single case. In conclusion, coding changes of the IL1RAPL1 gene do not appear to be associated with ASD in selected AGRE families with linkage evidence to the chromosome Xp22.11-p21.2 region. En ligne : http://dx.doi.org/10.1002/aur.195 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=141 [article] No evidence for IL1RAPL1 involvement in selected high-risk autism pedigrees from the AGRE data set [Texte imprimé et/ou numérique] / Kristina ALLEN-BRADY, Auteur ; Guiqing CAI, Auteur ; Dale CANNON, Auteur ; Reid ROBISON, Auteur ; William M. MCMAHON, Auteur ; Hilary H. COON, Auteur ; Joseph D. BUXBAUM, Auteur . - 2011 . - p.293-296. Langues : Anglais (eng) in Autism Research > 4-4 (August 2011) . - p.293-296 Mots-clés : behavioral analysis of animal models  developmental neurobiology  sex differences  testosterone  androgen receptor Index. décimale : PER Périodiques Résumé : Finding predisposition genes for Autism Spectrum Disorder (ASD) has proven challenging, and new methods are needed to aid the process. Using pedigree structure as a strategy to identify ASD predisposition genes, we previously performed a genome-wide linkage scan of 86 selected families from the Autism Resource Exchange (AGRE) that appeared to inherit ASD in a dominant manner. We identified a suggestive linkage peak on chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene, a strong candidate gene for ASD. In this follow-up study, we sequenced the coding regions of the IL1RAPL1 gene in 14 male cases representing one case from each pedigree that showed at least nominal linkage evidence on per pedigree basis to the chromosome X region. We observed no deleterious mutations or deletions in the IL1RAPL1 gene in these 14 ASD cases. A SNP was identified in exon 2 in five cases and a variant of unknown significance was identified in intron 6 in a single case. In conclusion, coding changes of the IL1RAPL1 gene do not appear to be associated with ASD in selected AGRE families with linkage evidence to the chromosome Xp22.11-p21.2 region. En ligne : http://dx.doi.org/10.1002/aur.195 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=141

A unified theory of autism revisited: linkage evidence points to chromosome X using a high-risk subset of AGRE families / Kristina ALLEN-BRADY in Autism Research, 3-2 (April 2010)  

Public ISBD [article]  inAutism Research > 3-2 (April 2010) . - p.47-52 Titre : A unified theory of autism revisited: linkage evidence points to chromosome X using a high-risk subset of AGRE families Type de document : Texte imprimé et/ou numérique Auteurs : Kristina ALLEN-BRADY, Auteur ; William M. MCMAHON, Auteur ; Hilary H. COON, Auteur ; Dale CANNON, Auteur ; Reid ROBISON, Auteur Année de publication : 2010 Article en page(s) : p.47-52 Langues : Anglais (eng) Mots-clés : autism-spectrum-disorder genetic-linkage dominant-model pedigree-structure chromosome-Xp Index. décimale : PER Périodiques Résumé : Zhao et al. [[2007]] in their Unified Theory of Autism hypothesized that incidence of autism in males could be explained by essentially two types of family structures: majority of autism cases are from low-risk autism families with de novo mutations, and a minority of cases are from high-risk multiplex families, where risk to male offspring approximates 50% consistent with a dominant model and high penetrance. Using the Autism Genetic Resource Exchange (AGRE) data set, Zhao et al. identified 86 high-risk families with likely dominant transmission. As genotype data are now available for many members of the AGRE resource, the objective of this manuscript was to determine if dominant linkage evidence for an autism predisposition gene exists in these 86 high-risk families. HumanHap550K Illumina SNP data were available for 92% of 455 total family members in these 86 high-risk families. We performed a linkage analysis using a pruned subset of markers where markers in high linkage disequilibrium were removed. We observed a single suggestive peak (maximum LOD 2.01, maximum HLOD 2.08) under a dominant model on chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene. Mutations or deletions in IL1RAPL1 have been previously reported in three families with autism. In our study, 11 families contributed nominally (P<0.05, HLOD>0.588) to the chromosome X peak. These results demonstrate that identification of a more homogeneous subset of autism cases, which was based on family structure in this study, may help to identify, localize and further our understanding of autism predisposition genes. En ligne : http://dx.doi.org/10.1002/aur.119 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102 [article] A unified theory of autism revisited: linkage evidence points to chromosome X using a high-risk subset of AGRE families [Texte imprimé et/ou numérique] / Kristina ALLEN-BRADY, Auteur ; William M. MCMAHON, Auteur ; Hilary H. COON, Auteur ; Dale CANNON, Auteur ; Reid ROBISON, Auteur . - 2010 . - p.47-52. Langues : Anglais (eng) in Autism Research > 3-2 (April 2010) . - p.47-52 Mots-clés : autism-spectrum-disorder genetic-linkage dominant-model pedigree-structure chromosome-Xp Index. décimale : PER Périodiques Résumé : Zhao et al. [[2007]] in their Unified Theory of Autism hypothesized that incidence of autism in males could be explained by essentially two types of family structures: majority of autism cases are from low-risk autism families with de novo mutations, and a minority of cases are from high-risk multiplex families, where risk to male offspring approximates 50% consistent with a dominant model and high penetrance. Using the Autism Genetic Resource Exchange (AGRE) data set, Zhao et al. identified 86 high-risk families with likely dominant transmission. As genotype data are now available for many members of the AGRE resource, the objective of this manuscript was to determine if dominant linkage evidence for an autism predisposition gene exists in these 86 high-risk families. HumanHap550K Illumina SNP data were available for 92% of 455 total family members in these 86 high-risk families. We performed a linkage analysis using a pruned subset of markers where markers in high linkage disequilibrium were removed. We observed a single suggestive peak (maximum LOD 2.01, maximum HLOD 2.08) under a dominant model on chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene. Mutations or deletions in IL1RAPL1 have been previously reported in three families with autism. In our study, 11 families contributed nominally (P<0.05, HLOD>0.588) to the chromosome X peak. These results demonstrate that identification of a more homogeneous subset of autism cases, which was based on family structure in this study, may help to identify, localize and further our understanding of autism predisposition genes. En ligne : http://dx.doi.org/10.1002/aur.119 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=102

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