Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data / Olivia J. VEATCH in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data Type de document : texte imprimé Auteurs : Olivia J. VEATCH, Auteur ; Diego R. MAZZOTTI, Auteur ; Robert T. SCHULTZ, Auteur ; Ted ABEL, Auteur ; Jacob J. MICHAELSON, Auteur ; Edward S. BRODKIN, Auteur ; Birkan TUNC, Auteur ; Susan G. ASSOULINE, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Beth A. MALOW, Auteur ; James S. SUTCLIFFE, Auteur ; Allan I. PACK, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Autism Spectrum Disorder/complications/genetics  Biological Phenomena  Child  Exome/genetics  Humans  Sleep Wake Disorders/complications/genetics  Exome Sequencing  Autism spectrum disorders  Genetic risk scores  Pleiotropy  Sleep duration  Systems biology Index. décimale : PER Périodiques Résumé : BACKGROUND: Numerous genes are implicated in autism spectrum disorder (ASD). ASD encompasses a wide-range and severity of symptoms and co-occurring conditions; however, the details of how genetic variation contributes to phenotypic differences are unclear. This creates a challenge for translating genetic evidence into clinically useful knowledge. Sleep disturbances are particularly prevalent co-occurring conditions in ASD, and genetics may inform treatment. Identifying convergent mechanisms with evidence for dysfunction that connect ASD and sleep biology could help identify better treatments for sleep disturbances in these individuals. METHODS: To identify mechanisms that influence risk for ASD and co-occurring sleep disturbances, we analyzed whole exome sequence data from individuals in the Simons Simplex Collection (n = 2380). We predicted protein damaging variants (PDVs) in genes currently implicated in either ASD or sleep duration in typically developing children. We predicted a network of ASD-related proteins with direct evidence for interaction with sleep duration-related proteins encoded by genes with PDVs. Overrepresentation analyses of Gene Ontology-defined biological processes were conducted on the resulting gene set. We calculated the likelihood of dysfunction in the top overrepresented biological process. We then tested if scores reflecting genetic dysfunction in the process were associated with parent-reported sleep duration. RESULTS: There were 29 genes with PDVs in the ASD dataset where variation was reported in the literature to be associated with both ASD and sleep duration. A network of 108 proteins encoded by ASD and sleep duration candidate genes with PDVs was identified. The mechanism overrepresented in PDV-containing genes that encode proteins in the interaction network with the most evidence for dysfunction was cerebral cortex development (GO:0,021,987). Scores reflecting dysfunction in this process were associated with sleep durations; the largest effects were observed in adolescents (p = 4.65 × 10(-3)). CONCLUSIONS: Our bioinformatic-driven approach detected a biological process enriched for genes encoding a protein-protein interaction network linking ASD gene products with sleep duration gene products where accumulation of potentially damaging variants in individuals with ASD was associated with sleep duration as reported by the parents. Specifically, genetic dysfunction impacting development of the cerebral cortex may affect sleep by disrupting sleep homeostasis which is evidenced to be regulated by this brain region. Future functional assessments and objective measurements of sleep in adolescents with ASD could provide the basis for more informed treatment of sleep problems in these individuals. En ligne : https://dx.doi.org/10.1186/s11689-022-09448-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Calculating genetic risk for dysfunction in pleiotropic biological processes using whole exome sequencing data [texte imprimé] / Olivia J. VEATCH, Auteur ; Diego R. MAZZOTTI, Auteur ; Robert T. SCHULTZ, Auteur ; Ted ABEL, Auteur ; Jacob J. MICHAELSON, Auteur ; Edward S. BRODKIN, Auteur ; Birkan TUNC, Auteur ; Susan G. ASSOULINE, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Beth A. MALOW, Auteur ; James S. SUTCLIFFE, Auteur ; Allan I. PACK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Adolescent  Autism Spectrum Disorder/complications/genetics  Biological Phenomena  Child  Exome/genetics  Humans  Sleep Wake Disorders/complications/genetics  Exome Sequencing  Autism spectrum disorders  Genetic risk scores  Pleiotropy  Sleep duration  Systems biology Index. décimale : PER Périodiques Résumé : BACKGROUND: Numerous genes are implicated in autism spectrum disorder (ASD). ASD encompasses a wide-range and severity of symptoms and co-occurring conditions; however, the details of how genetic variation contributes to phenotypic differences are unclear. This creates a challenge for translating genetic evidence into clinically useful knowledge. Sleep disturbances are particularly prevalent co-occurring conditions in ASD, and genetics may inform treatment. Identifying convergent mechanisms with evidence for dysfunction that connect ASD and sleep biology could help identify better treatments for sleep disturbances in these individuals. METHODS: To identify mechanisms that influence risk for ASD and co-occurring sleep disturbances, we analyzed whole exome sequence data from individuals in the Simons Simplex Collection (n = 2380). We predicted protein damaging variants (PDVs) in genes currently implicated in either ASD or sleep duration in typically developing children. We predicted a network of ASD-related proteins with direct evidence for interaction with sleep duration-related proteins encoded by genes with PDVs. Overrepresentation analyses of Gene Ontology-defined biological processes were conducted on the resulting gene set. We calculated the likelihood of dysfunction in the top overrepresented biological process. We then tested if scores reflecting genetic dysfunction in the process were associated with parent-reported sleep duration. RESULTS: There were 29 genes with PDVs in the ASD dataset where variation was reported in the literature to be associated with both ASD and sleep duration. A network of 108 proteins encoded by ASD and sleep duration candidate genes with PDVs was identified. The mechanism overrepresented in PDV-containing genes that encode proteins in the interaction network with the most evidence for dysfunction was cerebral cortex development (GO:0,021,987). Scores reflecting dysfunction in this process were associated with sleep durations; the largest effects were observed in adolescents (p = 4.65 × 10(-3)). CONCLUSIONS: Our bioinformatic-driven approach detected a biological process enriched for genes encoding a protein-protein interaction network linking ASD gene products with sleep duration gene products where accumulation of potentially damaging variants in individuals with ASD was associated with sleep duration as reported by the parents. Specifically, genetic dysfunction impacting development of the cerebral cortex may affect sleep by disrupting sleep homeostasis which is evidenced to be regulated by this brain region. Future functional assessments and objective measurements of sleep in adolescents with ASD could provide the basis for more informed treatment of sleep problems in these individuals. En ligne : https://dx.doi.org/10.1186/s11689-022-09448-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts / Brooke G. MCKENNA in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 43 p. Titre : Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts Type de document : texte imprimé Auteurs : Brooke G. MCKENNA, Auteur ; Ying HUANG, Auteur ; Kévin VERVIER, Auteur ; Dabney HOFAMMANN, Auteur ; Mary CAFFERATA, Auteur ; Seima AL-MOMANI, Auteur ; Florencia LOWENTHAL, Auteur ; Angela ZHANG, Auteur ; Jin-Young KOH, Auteur ; Savantha THENUWARA, Auteur ; Leo BRUEGGEMAN, Auteur ; Ethan BAHL, Auteur ; Tanner KOOMAR, Auteur ; Natalie POTTSCHMIDT, Auteur ; Taylor KALMUS, Auteur ; Lucas CASTEN, Auteur ; Taylor R. THOMAS, Auteur ; Jacob J. MICHAELSON, Auteur Article en page(s) : 43 p. Langues : Anglais (eng) Mots-clés : Androgen exposure  Autism spectrum disorder  Masculinity  Neurodevelopment  Social functioning Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. METHODS: Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. RESULTS: We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all [Formula: see text]), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text], respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ([Formula: see text], [Formula: see text]), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ([Formula: see text], [Formula: see text]). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ([Formula: see text], [Formula: see text], and [Formula: see text], [Formula: see text] for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: [Formula: see text]; testosterone: [Formula: see text] from 0.1%-ile to 99.9%-ile; SHBG: [Formula: see text] from 0.1%-ile to 99.9%-ile). LIMITATIONS: In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. CONCLUSIONS: These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females. En ligne : http://dx.doi.org/10.1186/s13229-021-00450-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts [texte imprimé] / Brooke G. MCKENNA, Auteur ; Ying HUANG, Auteur ; Kévin VERVIER, Auteur ; Dabney HOFAMMANN, Auteur ; Mary CAFFERATA, Auteur ; Seima AL-MOMANI, Auteur ; Florencia LOWENTHAL, Auteur ; Angela ZHANG, Auteur ; Jin-Young KOH, Auteur ; Savantha THENUWARA, Auteur ; Leo BRUEGGEMAN, Auteur ; Ethan BAHL, Auteur ; Tanner KOOMAR, Auteur ; Natalie POTTSCHMIDT, Auteur ; Taylor KALMUS, Auteur ; Lucas CASTEN, Auteur ; Taylor R. THOMAS, Auteur ; Jacob J. MICHAELSON, Auteur . - 43 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 43 p. Mots-clés : Androgen exposure  Autism spectrum disorder  Masculinity  Neurodevelopment  Social functioning Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. METHODS: Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. RESULTS: We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all [Formula: see text]), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text], respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ([Formula: see text], [Formula: see text]), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ([Formula: see text], [Formula: see text]). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ([Formula: see text], [Formula: see text], and [Formula: see text], [Formula: see text] for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: [Formula: see text]; testosterone: [Formula: see text] from 0.1%-ile to 99.9%-ile; SHBG: [Formula: see text] from 0.1%-ile to 99.9%-ile). LIMITATIONS: In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. CONCLUSIONS: These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females. En ligne : http://dx.doi.org/10.1186/s13229-021-00450-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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