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Auteur Ziarih HAWI |
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Evaluating the regulatory function of non-coding autism-associated single nucleotide polymorphisms on gene expression in human brain tissue / Kealan PUGSLEY in Autism Research, 17-3 (March 2024)
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Titre : Evaluating the regulatory function of non-coding autism-associated single nucleotide polymorphisms on gene expression in human brain tissue Type de document : Texte imprimé et/ou numérique Auteurs : Kealan PUGSLEY, Auteur ; Atefeh NAMIPASHAKI, Auteur ; Mark A. BELLGROVE, Auteur ; Ziarih HAWI, Auteur Article en page(s) : p.467-481 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Abstract Common variants account for most of the estimated heritability associated with autism spectrum disorder (autism). Although several replicable single nucleotide polymorphisms (SNPs) for the condition have been detected using genome-wide association study (GWAS) methodologies, their pathophysiological relevance remains elusive. Examining this is complicated, however, as all detected loci are situated within non-coding regions of the genome. It is therefore likely that they possess roles of regulatory function as opposed to directly affecting gene coding sequences. To bridge the gap between SNP discovery and mechanistic insight, we applied a comprehensive bioinformatic pipeline to functionally annotate autism-associated polymorphisms and their non-coding linkage disequilibrium (i.e., non-randomly associated) partners. We identified 82 DNA variants of probable regulatory function that may contribute to autism pathogenesis. To validate these predictions, we measured the impact of 11 high-confidence candidates and their GWAS linkage disequilibrium partners on gene expression in human brain tissue from Autistic and non-Autistic donors. Although a small number of the surveyed variants exhibited measurable influence on gene expression as determined via quantitative polymerase chain reaction, these did not survive correction for multiple comparisons. Additionally, no significant genotype-by-diagnosis effects were observed for any of the SNP-gene associations. We contend that this may reflect an inability to effectively capture the modest, neurodevelopmental-specific impact of individual variants on biological dysregulation in available post-mortem tissue samples, as well as limitations in the existing autism GWAS data. En ligne : https://doi.org/10.1002/aur.3101 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=525
in Autism Research > 17-3 (March 2024) . - p.467-481[article] Evaluating the regulatory function of non-coding autism-associated single nucleotide polymorphisms on gene expression in human brain tissue [Texte imprimé et/ou numérique] / Kealan PUGSLEY, Auteur ; Atefeh NAMIPASHAKI, Auteur ; Mark A. BELLGROVE, Auteur ; Ziarih HAWI, Auteur . - p.467-481.
Langues : Anglais (eng)
in Autism Research > 17-3 (March 2024) . - p.467-481
Index. décimale : PER Périodiques Résumé : Abstract Common variants account for most of the estimated heritability associated with autism spectrum disorder (autism). Although several replicable single nucleotide polymorphisms (SNPs) for the condition have been detected using genome-wide association study (GWAS) methodologies, their pathophysiological relevance remains elusive. Examining this is complicated, however, as all detected loci are situated within non-coding regions of the genome. It is therefore likely that they possess roles of regulatory function as opposed to directly affecting gene coding sequences. To bridge the gap between SNP discovery and mechanistic insight, we applied a comprehensive bioinformatic pipeline to functionally annotate autism-associated polymorphisms and their non-coding linkage disequilibrium (i.e., non-randomly associated) partners. We identified 82 DNA variants of probable regulatory function that may contribute to autism pathogenesis. To validate these predictions, we measured the impact of 11 high-confidence candidates and their GWAS linkage disequilibrium partners on gene expression in human brain tissue from Autistic and non-Autistic donors. Although a small number of the surveyed variants exhibited measurable influence on gene expression as determined via quantitative polymerase chain reaction, these did not survive correction for multiple comparisons. Additionally, no significant genotype-by-diagnosis effects were observed for any of the SNP-gene associations. We contend that this may reflect an inability to effectively capture the modest, neurodevelopmental-specific impact of individual variants on biological dysregulation in available post-mortem tissue samples, as well as limitations in the existing autism GWAS data. En ligne : https://doi.org/10.1002/aur.3101 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=525