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DNA Methylation Analysis of HTR2A Regulatory Region in Leukocytes of Autistic Subjects / Dubravka HRANILOVIC in Autism Research, 9-2 (February 2016)
[article]
Titre : DNA Methylation Analysis of HTR2A Regulatory Region in Leukocytes of Autistic Subjects Type de document : Texte imprimé et/ou numérique Auteurs : Dubravka HRANILOVIC, Auteur ; Sofia BLAZEVIC, Auteur ; Jasminka STEFULJ, Auteur ; Peter ZILL, Auteur Article en page(s) : p.204-209 Langues : Anglais (eng) Mots-clés : autism serotonin HTR2A DNA methylation epigenetics Index. décimale : PER Périodiques Résumé : Disturbed brain and peripheral serotonin homeostasis is often found in subjects with autism spectrum disorder (ASD). The role of the serotonin receptor 2A (HTR2A) in the regulation of central and peripheral serotonin homeostasis, as well as its altered expression in autistic subjects, have implicated the HTR2A gene as a major candidate for the serotonin disturbance seen in autism. Several studies, yielding so far inconclusive results, have attempted to associate autism with a functional SNP ?1438 G/A (rs6311) in the HTR2A promoter region, while possible contribution of epigenetic mechanisms, such as DNA methylation, to HTR2A dysregulation in autism has not yet been investigated. In this study, we compared the mean DNA methylation within the regulatory region of the HTR2A gene between autistic and control subjects. DNA methylation was analysed in peripheral blood leukocytes using bisulfite conversion and sequencing of the HTR2A region containing rs6311 polymorphism. Autistic subjects of rs6311 AG genotype displayed higher mean methylation levels within the analysed region than the corresponding controls (P?0.05), while there was no statistically significant difference for AA and GG carriers. Our study provides preliminary evidence for increased HTR2A promoter methylation in leukocytes of a portion of adult autistic subjects, indicating that epigenetic mechanisms might contribute to HTR2A dysregulation observed in individuals with ASD. En ligne : http://dx.doi.org/10.1002/aur.1519 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=282
in Autism Research > 9-2 (February 2016) . - p.204-209[article] DNA Methylation Analysis of HTR2A Regulatory Region in Leukocytes of Autistic Subjects [Texte imprimé et/ou numérique] / Dubravka HRANILOVIC, Auteur ; Sofia BLAZEVIC, Auteur ; Jasminka STEFULJ, Auteur ; Peter ZILL, Auteur . - p.204-209.
Langues : Anglais (eng)
in Autism Research > 9-2 (February 2016) . - p.204-209
Mots-clés : autism serotonin HTR2A DNA methylation epigenetics Index. décimale : PER Périodiques Résumé : Disturbed brain and peripheral serotonin homeostasis is often found in subjects with autism spectrum disorder (ASD). The role of the serotonin receptor 2A (HTR2A) in the regulation of central and peripheral serotonin homeostasis, as well as its altered expression in autistic subjects, have implicated the HTR2A gene as a major candidate for the serotonin disturbance seen in autism. Several studies, yielding so far inconclusive results, have attempted to associate autism with a functional SNP ?1438 G/A (rs6311) in the HTR2A promoter region, while possible contribution of epigenetic mechanisms, such as DNA methylation, to HTR2A dysregulation in autism has not yet been investigated. In this study, we compared the mean DNA methylation within the regulatory region of the HTR2A gene between autistic and control subjects. DNA methylation was analysed in peripheral blood leukocytes using bisulfite conversion and sequencing of the HTR2A region containing rs6311 polymorphism. Autistic subjects of rs6311 AG genotype displayed higher mean methylation levels within the analysed region than the corresponding controls (P?0.05), while there was no statistically significant difference for AA and GG carriers. Our study provides preliminary evidence for increased HTR2A promoter methylation in leukocytes of a portion of adult autistic subjects, indicating that epigenetic mechanisms might contribute to HTR2A dysregulation observed in individuals with ASD. En ligne : http://dx.doi.org/10.1002/aur.1519 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=282 Family-Based Clinical Associations and Functional Characterization of the Serotonin 2A Receptor Gene (HTR2A) in Autism Spectrum Disorder / Ryan M. SMITH in Autism Research, 7-4 (August 2014)
[article]
Titre : Family-Based Clinical Associations and Functional Characterization of the Serotonin 2A Receptor Gene (HTR2A) in Autism Spectrum Disorder Type de document : Texte imprimé et/ou numérique Auteurs : Ryan M. SMITH, Auteur ; Wesley BANKS, Auteur ; Emily HANSEN, Auteur ; Wolfgang SADEE, Auteur ; Gail E. HERMAN, Auteur Année de publication : 2014 Article en page(s) : p.459-467 Langues : Anglais (eng) Mots-clés : autism serotonin gene expression HTR2A rs6311 monoamine Index. décimale : PER Périodiques Résumé : The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor “A” allele of rs6311 to offspring with ASD (permuted P?=?0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5? untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5?UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk. En ligne : http://dx.doi.org/10.1002/aur.1383 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=238
in Autism Research > 7-4 (August 2014) . - p.459-467[article] Family-Based Clinical Associations and Functional Characterization of the Serotonin 2A Receptor Gene (HTR2A) in Autism Spectrum Disorder [Texte imprimé et/ou numérique] / Ryan M. SMITH, Auteur ; Wesley BANKS, Auteur ; Emily HANSEN, Auteur ; Wolfgang SADEE, Auteur ; Gail E. HERMAN, Auteur . - 2014 . - p.459-467.
Langues : Anglais (eng)
in Autism Research > 7-4 (August 2014) . - p.459-467
Mots-clés : autism serotonin gene expression HTR2A rs6311 monoamine Index. décimale : PER Périodiques Résumé : The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor “A” allele of rs6311 to offspring with ASD (permuted P?=?0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5? untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5?UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk. En ligne : http://dx.doi.org/10.1002/aur.1383 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=238 Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: a genetic association study / V. M. SINOPOLI in Journal of Child Psychology and Psychiatry, 60-12 (December 2019)
[article]
Titre : Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: a genetic association study Type de document : Texte imprimé et/ou numérique Auteurs : V. M. SINOPOLI, Auteur ; L. ERDMAN, Auteur ; C. L. BURTON, Auteur ; L. S. PARK, Auteur ; A. DUPUIS, Auteur ; J. SHAN, Auteur ; T. GOODALE, Auteur ; S. M. SHAHEEN, Auteur ; J. CROSBIE, Auteur ; Russell SCHACHAR, Auteur ; P. D. ARNOLD, Auteur Article en page(s) : p.1289-1299 Langues : Anglais (eng) Mots-clés : 5-httlpr Htr1b Htr2a Obsessive-compulsive disorder Slc6a4 genetic association phenotypic heterogeneity population-based serotonin genes serotonin system symptom dimensions Index. décimale : PER Périodiques Résumé : BACKGROUND: Serotonin system genes are commonly studied in obsessive-compulsive disorder (OCD), but genetic studies to date have produced inconsistent results, possibly because phenotypic heterogeneity has not been adequately accounted for. In this paper, we studied candidate serotonergic genes and homogenous phenotypic subgroups as presented through obsessive-compulsive (OC) trait dimensions in a general population of children and adolescents. We hypothesized that different serotonergic gene variants are associated with different OC trait dimensions and, furthermore, that they vary by sex. METHODS: Obsessive-compulsive trait dimensions (Cleaning/Contamination, Counting/Checking, Symmetry/Ordering, Superstition, Rumination, and Hoarding) were examined in a total of 5,213 pediatric participants in the community using the Toronto Obsessive-Compulsive Scale (TOCS). We genotyped candidate serotonin genes (directly genotyping the 5-HTTLPR polymorphism in SLC6A4 for 2018 individuals and using single nucleotide polymorphism (SNP) array data for genes SLC6A4, HTR2A, and HTR1B for 4711 individuals). We assessed the association between variants across these genes and each of the OC trait dimensions, within males and females separately. We analyzed OC traits as both (a) dichotomized based on a threshold value and (b) quantitative scores. RESULTS: The [LG + S] variant in 5-HTTLPR was significantly associated with hoarding in males (p-value of 0.003 and 0.004 for categorical and continuous analyses, respectively). There were no significant findings for 5-HTTLPR in females. Using SNP array data, there were significant findings for rumination in males for HTR2A SNPs (p-value of 1.04e-6 to 5.20e-6). CONCLUSIONS: This represents the first genetic association study of OC trait dimensions in a community-based pediatric sample. Our strongest results indicate that hoarding and rumination may be distinct in their association with serotonin gene variants and that serotonin gene variation may be specific to sex. Future genetic association studies in OCD should properly account for heterogeneity, using homogenous subgroups stratified by symptom dimension, sex, and age group. En ligne : http://dx.doi.org/10.1111/jcpp.13079 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=412
in Journal of Child Psychology and Psychiatry > 60-12 (December 2019) . - p.1289-1299[article] Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: a genetic association study [Texte imprimé et/ou numérique] / V. M. SINOPOLI, Auteur ; L. ERDMAN, Auteur ; C. L. BURTON, Auteur ; L. S. PARK, Auteur ; A. DUPUIS, Auteur ; J. SHAN, Auteur ; T. GOODALE, Auteur ; S. M. SHAHEEN, Auteur ; J. CROSBIE, Auteur ; Russell SCHACHAR, Auteur ; P. D. ARNOLD, Auteur . - p.1289-1299.
Langues : Anglais (eng)
in Journal of Child Psychology and Psychiatry > 60-12 (December 2019) . - p.1289-1299
Mots-clés : 5-httlpr Htr1b Htr2a Obsessive-compulsive disorder Slc6a4 genetic association phenotypic heterogeneity population-based serotonin genes serotonin system symptom dimensions Index. décimale : PER Périodiques Résumé : BACKGROUND: Serotonin system genes are commonly studied in obsessive-compulsive disorder (OCD), but genetic studies to date have produced inconsistent results, possibly because phenotypic heterogeneity has not been adequately accounted for. In this paper, we studied candidate serotonergic genes and homogenous phenotypic subgroups as presented through obsessive-compulsive (OC) trait dimensions in a general population of children and adolescents. We hypothesized that different serotonergic gene variants are associated with different OC trait dimensions and, furthermore, that they vary by sex. METHODS: Obsessive-compulsive trait dimensions (Cleaning/Contamination, Counting/Checking, Symmetry/Ordering, Superstition, Rumination, and Hoarding) were examined in a total of 5,213 pediatric participants in the community using the Toronto Obsessive-Compulsive Scale (TOCS). We genotyped candidate serotonin genes (directly genotyping the 5-HTTLPR polymorphism in SLC6A4 for 2018 individuals and using single nucleotide polymorphism (SNP) array data for genes SLC6A4, HTR2A, and HTR1B for 4711 individuals). We assessed the association between variants across these genes and each of the OC trait dimensions, within males and females separately. We analyzed OC traits as both (a) dichotomized based on a threshold value and (b) quantitative scores. RESULTS: The [LG + S] variant in 5-HTTLPR was significantly associated with hoarding in males (p-value of 0.003 and 0.004 for categorical and continuous analyses, respectively). There were no significant findings for 5-HTTLPR in females. Using SNP array data, there were significant findings for rumination in males for HTR2A SNPs (p-value of 1.04e-6 to 5.20e-6). CONCLUSIONS: This represents the first genetic association study of OC trait dimensions in a community-based pediatric sample. Our strongest results indicate that hoarding and rumination may be distinct in their association with serotonin gene variants and that serotonin gene variation may be specific to sex. Future genetic association studies in OCD should properly account for heterogeneity, using homogenous subgroups stratified by symptom dimension, sex, and age group. En ligne : http://dx.doi.org/10.1111/jcpp.13079 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=412