Autism spectrum disorder and brain volume link through a set of mTOR-related genes / Martina ARENELLA in Journal of Child Psychology and Psychiatry, 64-7 (July 2023)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 64-7 (July 2023) . - p.1007-1014 Titre : Autism spectrum disorder and brain volume link through a set of mTOR-related genes Type de document : texte imprimé Auteurs : Martina ARENELLA, Auteur ; Nina R. MOTA, Auteur ; Mariel W.A. TEUNISSEN, Auteur ; Han G. BRUNNER, Auteur ; Janita B. BRALTEN, Auteur Article en page(s) : p.1007-1014 Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  genetics  brain volume  mammalian target of rapamycin  stratified genetic correlation Index. décimale : PER Périodiques Résumé : Background Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. Methods We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. Results Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). Conclusions This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD. En ligne : https://doi.org/10.1111/jcpp.13783 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=508 [article] Autism spectrum disorder and brain volume link through a set of mTOR-related genes [texte imprimé] / Martina ARENELLA, Auteur ; Nina R. MOTA, Auteur ; Mariel W.A. TEUNISSEN, Auteur ; Han G. BRUNNER, Auteur ; Janita B. BRALTEN, Auteur . - p.1007-1014. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 64-7 (July 2023) . - p.1007-1014 Mots-clés : Autism spectrum disorders  genetics  brain volume  mammalian target of rapamycin  stratified genetic correlation Index. décimale : PER Périodiques Résumé : Background Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. Methods We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. Results Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). Conclusions This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD. En ligne : https://doi.org/10.1111/jcpp.13783 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=508

Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits / Martina ARENELLA in Autism, 26-2 (February 2022)  

Public ISBD [article]  inAutism > 26-2 (February 2022) . - p.361-372 Titre : Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits Type de document : texte imprimé Auteurs : Martina ARENELLA, Auteur ; Gemma CADBY, Auteur ; Ward DE WITTE, Auteur ; Rebecca M. JONES, Auteur ; Andrew J.O. WHITEHOUSE, Auteur ; Eric K. MOSES, Auteur ; Alex FORNITO, Auteur ; Mark A. BELLGROVE, Auteur ; Ziarih HAWI, Auteur ; Beth P. JOHNSON, Auteur ; Jeggan TIEGO, Auteur ; Jan K. BUITELAAR, Auteur ; Lambertus A. KIEMENEY, Auteur ; Geert POELMANS, Auteur ; Janita B. BRALTEN, Auteur Article en page(s) : p.361-372 Langues : Anglais (eng) Mots-clés : autism spectrum disorders  genetics  immune system  molecular and cellular biology  conflicts of interest with respect to the research, authorship and/or publication of  this article: In the past 3?years, J.K.B. has been a consultant to, member of  advisory board of and speaker for Takeda/Shire, Roche, Medice, Novartis, Angelini  and Servier. He is not an employee of any of these companies, and a stock  shareholder of any of these companies. He has no other financial or material  support, including expert testimony, patients and royalties. G.P. is the director of  Drug Target ID, Ltd. The other authors declare no conflict of interest. Index. décimale : PER Périodiques Résumé : Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients. En ligne : http://dx.doi.org/10.1177/13623613211019547 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=452 [article] Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits [texte imprimé] / Martina ARENELLA, Auteur ; Gemma CADBY, Auteur ; Ward DE WITTE, Auteur ; Rebecca M. JONES, Auteur ; Andrew J.O. WHITEHOUSE, Auteur ; Eric K. MOSES, Auteur ; Alex FORNITO, Auteur ; Mark A. BELLGROVE, Auteur ; Ziarih HAWI, Auteur ; Beth P. JOHNSON, Auteur ; Jeggan TIEGO, Auteur ; Jan K. BUITELAAR, Auteur ; Lambertus A. KIEMENEY, Auteur ; Geert POELMANS, Auteur ; Janita B. BRALTEN, Auteur . - p.361-372. Langues : Anglais (eng) in Autism > 26-2 (February 2022) . - p.361-372 Mots-clés : autism spectrum disorders  genetics  immune system  molecular and cellular biology  conflicts of interest with respect to the research, authorship and/or publication of  this article: In the past 3?years, J.K.B. has been a consultant to, member of  advisory board of and speaker for Takeda/Shire, Roche, Medice, Novartis, Angelini  and Servier. He is not an employee of any of these companies, and a stock  shareholder of any of these companies. He has no other financial or material  support, including expert testimony, patients and royalties. G.P. is the director of  Drug Target ID, Ltd. The other authors declare no conflict of interest. Index. décimale : PER Périodiques Résumé : Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients. En ligne : http://dx.doi.org/10.1177/13623613211019547 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=452

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