Protein-Altering Variants' Analysis in Autism Subgroups Uncovers Early Brain-Expressed Gene Modules Relevant to Autism Pathophysiology / Gaia SCACCABAROZZI in Autism Research, 18-8 (August 2025)  

Public ISBD [article]  inAutism Research > 18-8 (August 2025) . - p.1535-1549 Titre : Protein-Altering Variants' Analysis in Autism Subgroups Uncovers Early Brain-Expressed Gene Modules Relevant to Autism Pathophysiology Type de document : texte imprimé Auteurs : Gaia SCACCABAROZZI, Auteur ; Luca FUMAGALLI, Auteur ; Maddalena MAMBRETTI, Auteur ; Roberto GIORDA, Auteur ; Marco VILLA, Auteur ; Silvia BUSTI CECCARELLI, Auteur ; Laura VILLA, Auteur ; Elisa MANI, Auteur ; Maria NOBILE, Auteur ; Massimo MOLTENI, Auteur ; Uberto POZZOLI, Auteur ; Alessandro CRIPPA, Auteur Article en page(s) : p.1535-1549 Langues : Anglais (eng) Mots-clés : autism  brain expression  genetics  heterogeneity  protein-altering variants Index. décimale : PER Périodiques Résumé : ABSTRACT Understanding the functional implications of genes' variants in autism heterogeneity is challenging. Gene set analysis examines the cumulative effect of multiple functionally converging genes. Here we explored whether a multi-step analysis could identify gene sets with different loads of protein-altering variants (PAVs) between two subgroups of autistic children. After subdividing our sample (n 71, 3 12 years) based on higher (> 80; n 43) and lower (? 80; n 28) intelligence quotient (IQ), a gene set variant enrichment analysis identified gene sets with significantly different incidence of PAVs between the two subgroups of autistic children. Significant gene sets were then clustered into modules of genes. Their brain expression was investigated according to the BrainSpan Atlas of the Developing Human Brain. Next, we extended each module by selecting the genes that were spatio-temporally co-expressed in the developing brain and physically interacting with those in modules. Last, we explored the incidence of autism susceptibility genes within original and extended modules. Our analysis identified 38 significant gene sets (FDR, q?< 0.05). They clustered in four modules involved in ion cell communication, neurocognition, gastrointestinal function, and immune system. Those modules were highly expressed in specific brain structures across development. Spatio-temporal brain co-expression and physical interactions identified extended genes' clusters with over-represented autism susceptibility genes. Overall, our unbiased approach identified modules of genes functionally relevant to autism pathophysiology, possibly implicating them in phenotypic variability across subgroups. The findings also suggest that autism diversity likely originates from multiple interacting pathways. Future research could leverage this approach to identify genetic pathways relevant to autism subtyping. En ligne : https://doi.org/10.1002/aur.70086 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=566 [article] Protein-Altering Variants' Analysis in Autism Subgroups Uncovers Early Brain-Expressed Gene Modules Relevant to Autism Pathophysiology [texte imprimé] / Gaia SCACCABAROZZI, Auteur ; Luca FUMAGALLI, Auteur ; Maddalena MAMBRETTI, Auteur ; Roberto GIORDA, Auteur ; Marco VILLA, Auteur ; Silvia BUSTI CECCARELLI, Auteur ; Laura VILLA, Auteur ; Elisa MANI, Auteur ; Maria NOBILE, Auteur ; Massimo MOLTENI, Auteur ; Uberto POZZOLI, Auteur ; Alessandro CRIPPA, Auteur . - p.1535-1549. Langues : Anglais (eng) in Autism Research > 18-8 (August 2025) . - p.1535-1549 Mots-clés : autism  brain expression  genetics  heterogeneity  protein-altering variants Index. décimale : PER Périodiques Résumé : ABSTRACT Understanding the functional implications of genes' variants in autism heterogeneity is challenging. Gene set analysis examines the cumulative effect of multiple functionally converging genes. Here we explored whether a multi-step analysis could identify gene sets with different loads of protein-altering variants (PAVs) between two subgroups of autistic children. After subdividing our sample (n 71, 3 12 years) based on higher (> 80; n 43) and lower (? 80; n 28) intelligence quotient (IQ), a gene set variant enrichment analysis identified gene sets with significantly different incidence of PAVs between the two subgroups of autistic children. Significant gene sets were then clustered into modules of genes. Their brain expression was investigated according to the BrainSpan Atlas of the Developing Human Brain. Next, we extended each module by selecting the genes that were spatio-temporally co-expressed in the developing brain and physically interacting with those in modules. Last, we explored the incidence of autism susceptibility genes within original and extended modules. Our analysis identified 38 significant gene sets (FDR, q?< 0.05). They clustered in four modules involved in ion cell communication, neurocognition, gastrointestinal function, and immune system. Those modules were highly expressed in specific brain structures across development. Spatio-temporal brain co-expression and physical interactions identified extended genes' clusters with over-represented autism susceptibility genes. Overall, our unbiased approach identified modules of genes functionally relevant to autism pathophysiology, possibly implicating them in phenotypic variability across subgroups. The findings also suggest that autism diversity likely originates from multiple interacting pathways. Future research could leverage this approach to identify genetic pathways relevant to autism subtyping. En ligne : https://doi.org/10.1002/aur.70086 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=566

Sex-dimorphic pathways in the associations between maternal trait anxiety, infant BDNF methylation, and negative emotionality / Serena GRUMI ; Fabiana MAMBRETTI ; Marco VILLA ; Roberto GIORDA ; Matteo BORDONI ; Orietta PANSARASA ; Renato BORGATTI ; Livio PROVENZI in Development and Psychopathology, 36-2 (May 2024)  

Public ISBD [article]  inDevelopment and Psychopathology > 36-2 (May 2024) . - p.908-918 Titre : Sex-dimorphic pathways in the associations between maternal trait anxiety, infant BDNF methylation, and negative emotionality Type de document : texte imprimé Auteurs : Serena GRUMI, Auteur ; Fabiana MAMBRETTI, Auteur ; Marco VILLA, Auteur ; Roberto GIORDA, Auteur ; Matteo BORDONI, Auteur ; Orietta PANSARASA, Auteur ; Renato BORGATTI, Auteur ; Livio PROVENZI, Auteur Article en page(s) : p.908-918 Langues : Anglais (eng) Mots-clés : Anxiety  Brain-derived neurotrophic factor  Methylation  Pregnancy  Temperament Index. décimale : PER Périodiques Résumé : Maternal antenatal anxiety is an emerging risk factor for child emotional development. Both sex and epigenetic mechanisms, such as DNA methylation, may contribute to the embedding of maternal distress into emotional outcomes. Here, we investigated sex-dependent patterns in the association between antenatal maternal trait anxiety, methylation of the brain-derived neurotrophic factor gene (BDNF DNAm), and infant negative emotionality (NE). Mother-infant dyads (N = 276) were recruited at delivery. Maternal trait anxiety, as a marker of antenatal chronic stress exposure, was assessed soon after delivery using the Stait-Trait Anxiety Inventory (STAI-Y). Infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells whereas infants' NE was assessed at 3 (N = 225) and 6 months (N = 189) using the Infant Behavior Questionnaire-Revised (IBQ-R). Hierarchical linear analyses showed that higher maternal antenatal anxiety was associated with greater 6-month-olds' NE. Furthermore, maternal antenatal anxiety predicted greater infants' BDNF DNAm in five CpG sites in males but not in females. Higher methylation at these sites was associated with greater 3-to-6-month NE increase, independently of infants' sex. Maternal antenatal anxiety emerged as a risk factor for infant?s NE. BDNF DNAm might mediate this effect in males. These results may inform the development of strategies to promote mothers and infants' emotional well-being. En ligne : https://dx.doi.org/10.1017/S0954579423000172 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=528 [article] Sex-dimorphic pathways in the associations between maternal trait anxiety, infant BDNF methylation, and negative emotionality [texte imprimé] / Serena GRUMI, Auteur ; Fabiana MAMBRETTI, Auteur ; Marco VILLA, Auteur ; Roberto GIORDA, Auteur ; Matteo BORDONI, Auteur ; Orietta PANSARASA, Auteur ; Renato BORGATTI, Auteur ; Livio PROVENZI, Auteur . - p.908-918. Langues : Anglais (eng) in Development and Psychopathology > 36-2 (May 2024) . - p.908-918 Mots-clés : Anxiety  Brain-derived neurotrophic factor  Methylation  Pregnancy  Temperament Index. décimale : PER Périodiques Résumé : Maternal antenatal anxiety is an emerging risk factor for child emotional development. Both sex and epigenetic mechanisms, such as DNA methylation, may contribute to the embedding of maternal distress into emotional outcomes. Here, we investigated sex-dependent patterns in the association between antenatal maternal trait anxiety, methylation of the brain-derived neurotrophic factor gene (BDNF DNAm), and infant negative emotionality (NE). Mother-infant dyads (N = 276) were recruited at delivery. Maternal trait anxiety, as a marker of antenatal chronic stress exposure, was assessed soon after delivery using the Stait-Trait Anxiety Inventory (STAI-Y). Infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells whereas infants' NE was assessed at 3 (N = 225) and 6 months (N = 189) using the Infant Behavior Questionnaire-Revised (IBQ-R). Hierarchical linear analyses showed that higher maternal antenatal anxiety was associated with greater 6-month-olds' NE. Furthermore, maternal antenatal anxiety predicted greater infants' BDNF DNAm in five CpG sites in males but not in females. Higher methylation at these sites was associated with greater 3-to-6-month NE increase, independently of infants' sex. Maternal antenatal anxiety emerged as a risk factor for infant?s NE. BDNF DNAm might mediate this effect in males. These results may inform the development of strategies to promote mothers and infants' emotional well-being. En ligne : https://dx.doi.org/10.1017/S0954579423000172 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=528

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