46 recherche sur le mot-clé 'Autism Spectrum Disorder/genetics'

Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis / Lukas S. SCHAFFER in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 46p. Titre : Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis Type de document : texte imprimé Auteurs : Lukas S. SCHAFFER, Auteur ; Sophie BREUNIG, Auteur ; Jeremy M. LAWRENCE, Auteur ; Isabelle F FOOTE, Auteur ; Andrew D. GROTZINGER, Auteur Article en page(s) : 46p. Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Genetic Predisposition to Disease  Attention Deficit Disorder with Hyperactivity/genetics  Phenotype  Transcriptome  Male  Female  Child  Polymorphism, Single Nucleotide  Latent Class Analysis  Attention-deficit/hyperactivity disorder  Autism spectrum disorder  Comorbidity  Genomic SEM  Multivariate genomics  Neurodevelopmental disorders  Psychiatric genetics Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways increase the likelihood of ASD independently of ADHD. METHODS: We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and childhood-diagnosed ADHD, decomposing the genetic variance for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 83 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD. RESULTS: We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, 34 of which were novel with respect to univariate analyses. These genes were overrepresented in skin-related pathologies. LIMITATIONS: Our study was limited by summary statistics derived exclusively from individuals of European ancestry. Additionally, using data based on a general ASD diagnosis limits our ability to understand genetic factors contributing to the pronounced clinical heterogeneity in ASD. CONCLUSIONS: Our findings delineate the unique genetic underpinnings of ASD that are independent of ADHD at the genome-wide, functional, and gene expression level of analysis. In addition, we identify novel associations previously masked by their diametric effects on ADHD. Collectively, these results provide insight into the processes that make ASD biologically unique. En ligne : https://dx.doi.org/10.1186/s13229-024-00624-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis [texte imprimé] / Lukas S. SCHAFFER, Auteur ; Sophie BREUNIG, Auteur ; Jeremy M. LAWRENCE, Auteur ; Isabelle F FOOTE, Auteur ; Andrew D. GROTZINGER, Auteur . - 46p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 46p. Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Genetic Predisposition to Disease  Attention Deficit Disorder with Hyperactivity/genetics  Phenotype  Transcriptome  Male  Female  Child  Polymorphism, Single Nucleotide  Latent Class Analysis  Attention-deficit/hyperactivity disorder  Autism spectrum disorder  Comorbidity  Genomic SEM  Multivariate genomics  Neurodevelopmental disorders  Psychiatric genetics Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways increase the likelihood of ASD independently of ADHD. METHODS: We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and childhood-diagnosed ADHD, decomposing the genetic variance for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 83 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD. RESULTS: We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, 34 of which were novel with respect to univariate analyses. These genes were overrepresented in skin-related pathologies. LIMITATIONS: Our study was limited by summary statistics derived exclusively from individuals of European ancestry. Additionally, using data based on a general ASD diagnosis limits our ability to understand genetic factors contributing to the pronounced clinical heterogeneity in ASD. CONCLUSIONS: Our findings delineate the unique genetic underpinnings of ASD that are independent of ADHD at the genome-wide, functional, and gene expression level of analysis. In addition, we identify novel associations previously masked by their diametric effects on ADHD. Collectively, these results provide insight into the processes that make ASD biologically unique. En ligne : https://dx.doi.org/10.1186/s13229-024-00624-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder / Michael YAO in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder Type de document : texte imprimé Auteurs : Michael YAO, Auteur ; Jason DANIELS, Auteur ; Luke GROSVENOR, Auteur ; Valerie MORRILL, Auteur ; Jason I. FEINBERG, Auteur ; Kelly M. BAKULSKI, Auteur ; Joseph PIVEN, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Craig NEWSCHAFFER, Auteur ; Kristen LYALL, Auteur ; Rebecca J. SCHMIDT, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Lisa A. CROEN, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur ; Heather VOLK, Auteur ; Kelly BENKE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Multifactorial Inheritance  Genetic Predisposition to Disease  Male  Female  Genotype  Polymorphism, Single Nucleotide  Autism spectrum disorder (ASD)  Information Loss  Polygenic scores (PGS) Index. décimale : PER Périodiques Résumé : BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. En ligne : https://dx.doi.org/10.1186/s11689-024-09571-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder [texte imprimé] / Michael YAO, Auteur ; Jason DANIELS, Auteur ; Luke GROSVENOR, Auteur ; Valerie MORRILL, Auteur ; Jason I. FEINBERG, Auteur ; Kelly M. BAKULSKI, Auteur ; Joseph PIVEN, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Craig NEWSCHAFFER, Auteur ; Kristen LYALL, Auteur ; Rebecca J. SCHMIDT, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Lisa A. CROEN, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur ; Heather VOLK, Auteur ; Kelly BENKE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Multifactorial Inheritance  Genetic Predisposition to Disease  Male  Female  Genotype  Polymorphism, Single Nucleotide  Autism spectrum disorder (ASD)  Information Loss  Polygenic scores (PGS) Index. décimale : PER Périodiques Résumé : BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. En ligne : https://dx.doi.org/10.1186/s11689-024-09571-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder / William FYKE in Autism Research, 14-9 (September 2021)  

Public ISBD [article]  inAutism Research > 14-9 (September 2021) . - p.1854-1872 Titre : Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder Type de document : texte imprimé Auteurs : William FYKE, Auteur ; Marika PREMOLI, Auteur ; Victor ECHEVERRY ALZATE, Auteur ; José A. LÓPEZ-MORENO, Auteur ; Valerie LEMAIRE-MAYO, Auteur ; Wim E. CRUSIO, Auteur ; Giovanni MARSICANO, Auteur ; M. WOHR, Auteur ; Susanna PIETROPAOLO, Auteur Article en page(s) : p.1854-1872 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Communication and social interaction in the cannabinoid-type 1 receptor null mouse: Implications for autism spectrum disorder [texte imprimé] / William FYKE, Auteur ; Marika PREMOLI, Auteur ; Victor ECHEVERRY ALZATE, Auteur ; José A. LÓPEZ-MORENO, Auteur ; Valerie LEMAIRE-MAYO, Auteur ; Wim E. CRUSIO, Auteur ; Giovanni MARSICANO, Auteur ; M. WOHR, Auteur ; Susanna PIETROPAOLO, Auteur . - p.1854-1872. Langues : Anglais (eng) in Autism Research > 14-9 (September 2021) . - p.1854-1872 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Communication  Disease Models, Animal  Female  Male  Mice  Mice, Knockout  Receptor, Cannabinoid, CB1/genetics  Social Behavior  Social Interaction  cannabinoid receptor  mouse models  phenotype  sex differences  ultrasounds Index. décimale : PER Périodiques Résumé : Clinical and preclinical findings have suggested a role of the endocannabinoid system (ECS) in the etiopathology of autism spectrum disorder (ASD). Previous mouse studies have investigated the role of ECS in several behavioral domains; however, none of them has performed an extensive assessment of social and communication behaviors, that is, the main core features of ASD. This study employed a mouse line lacking the primary endocannabinoid receptor (CB1r) and characterized ultrasonic communication and social interaction in CB1(-/-) , CB1(+/-) , and CB1(+/+) males and females. Quantitative and qualitative alterations in ultrasonic vocalizations (USVs) were observed in CB1 null mice both during early development (i.e., between postnatal days 4 and 10), and at adulthood (i.e., at 3 months of age). Adult mutants also showed marked deficits in social interest in the three-chamber test and social investigation in the direct social interaction test. These behavioral alterations were mostly observed in both sexes and appeared more marked in CB1(-/-) than CB1(+/-) mutant mice. Importantly, the adult USV alterations could not be attributed to differences in anxiety or sensorimotor abilities, as assessed by the elevated plus maze and auditory startle tests. Our findings demonstrate the role of CB1r in social communication and behavior, supporting the use of the CB1 full knockout mouse in preclinical research on these ASD-relevant core domains. LAY SUMMARY: The endocannabinoid system (ECS) is important for brain development and neural function and is therefore likely to be involved in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Here we investigated changes in social behavior and communication, which are core features of ASD, in male and female mice lacking the chief receptor of this system. Our results show that loss of this receptor results in several changes in social behavior and communication both during early development and in adulthood, thus supporting the role of the ECS in these ASD-core behavioral domains. En ligne : http://dx.doi.org/10.1002/aur.2562 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Endophenotype trait domains for advancing gene discovery in autism spectrum disorder / Matthew W. MOSCONI in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Endophenotype trait domains for advancing gene discovery in autism spectrum disorder Type de document : texte imprimé Auteurs : Matthew W. MOSCONI, Auteur ; Cassandra J. STEVENS, Auteur ; Kathryn E. UNRUH, Auteur ; Robin SHAFER, Auteur ; Jed T. ELISON, Auteur Langues : Anglais (eng) Mots-clés : Infant  Humans  Autism Spectrum Disorder/genetics  Endophenotypes  Language  Neurodevelopmental Disorders  Genetic Association Studies Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals with ASD, it is likely that the primary causes involve multiple common inherited variants that individually account for only small levels of variation in phenotypic outcomes. This genetic landscape creates a major challenge for detecting small but important pathogenic effects associated with ASD. To address similar challenges, separate fields of medicine have identified endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition and leveraged the study of these traits to map polygenic mechanisms and advance more personalized therapeutic strategies for complex diseases. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to psychiatric and developmental disorders because they are embedded within the causal chain between genotype and clinical phenotype, and they are more proximal to the action of the gene(s) than behavioral traits. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies. In this review, we argue that advancing knowledge of the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs with measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. We also emphasize that clarification of endophenotypic traits necessarily will involve integration of transdiagnostic approaches as candidate traits likely reflect liability for multiple clinical conditions and often are agnostic to diagnostic boundaries. Multiple candidate endophenotypes associated with ASD likelihood are described, and we propose a new focus on the analysis of "endophenotype trait domains" (ETDs), or traits measured across multiple levels (e.g., molecular, cellular, neural system, neuropsychological) along the causal pathway from genes to behavior. To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We also present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical autistic traits, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes associated with ASD as well as overlapping neurodevelopmental disorders. En ligne : https://dx.doi.org/10.1186/s11689-023-09511-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Endophenotype trait domains for advancing gene discovery in autism spectrum disorder [texte imprimé] / Matthew W. MOSCONI, Auteur ; Cassandra J. STEVENS, Auteur ; Kathryn E. UNRUH, Auteur ; Robin SHAFER, Auteur ; Jed T. ELISON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Infant  Humans  Autism Spectrum Disorder/genetics  Endophenotypes  Language  Neurodevelopmental Disorders  Genetic Association Studies Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals with ASD, it is likely that the primary causes involve multiple common inherited variants that individually account for only small levels of variation in phenotypic outcomes. This genetic landscape creates a major challenge for detecting small but important pathogenic effects associated with ASD. To address similar challenges, separate fields of medicine have identified endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition and leveraged the study of these traits to map polygenic mechanisms and advance more personalized therapeutic strategies for complex diseases. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to psychiatric and developmental disorders because they are embedded within the causal chain between genotype and clinical phenotype, and they are more proximal to the action of the gene(s) than behavioral traits. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies. In this review, we argue that advancing knowledge of the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs with measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. We also emphasize that clarification of endophenotypic traits necessarily will involve integration of transdiagnostic approaches as candidate traits likely reflect liability for multiple clinical conditions and often are agnostic to diagnostic boundaries. Multiple candidate endophenotypes associated with ASD likelihood are described, and we propose a new focus on the analysis of "endophenotype trait domains" (ETDs), or traits measured across multiple levels (e.g., molecular, cellular, neural system, neuropsychological) along the causal pathway from genes to behavior. To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We also present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical autistic traits, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes associated with ASD as well as overlapping neurodevelopmental disorders. En ligne : https://dx.doi.org/10.1186/s11689-023-09511-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes / Mohammed UDDIN ; Joris A. VELTMAN ; Sara WELLS ; Christopher MORRIS ; Marc WOODBURY-SMITH in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 5 Titre : Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes Type de document : texte imprimé Auteurs : Mohammed UDDIN, Auteur ; Joris A. VELTMAN, Auteur ; Sara WELLS, Auteur ; Christopher MORRIS, Auteur ; Marc WOODBURY-SMITH, Auteur Article en page(s) : 5 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Humans  Macaca mulatta/genetics  Evolution, Molecular  Genome  Phenotype  Genetic Predisposition to Disease  Primates/genetics  Autism spectrum disorder  Gsea  Genetic constraint  Primate model  Whole genome sequencing  mGAP database protocols adhered to the NIH and the Guide for Use and Care of  Laboratory Animals and were approved by the Oregon Health & Sciences University  Animal Utilization and Care Committee [22]. Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Significant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. METHODS: We used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. RESULTS: We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4 * 10(- 27)). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1 * 10(- 46)), epilepsy (p = 2.1 * 10(- 33)) and schizophrenia (p = 4.2 * 10(- 45)), and for an overlapping neurodevelopmental gene set (p = 4.0 * 10(- 10)). LIMITATIONS: The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. CONCLUSION: The presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions. En ligne : https://dx.doi.org/10.1186/s13229-024-00633-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes [texte imprimé] / Mohammed UDDIN, Auteur ; Joris A. VELTMAN, Auteur ; Sara WELLS, Auteur ; Christopher MORRIS, Auteur ; Marc WOODBURY-SMITH, Auteur . - 5. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 5 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Humans  Macaca mulatta/genetics  Evolution, Molecular  Genome  Phenotype  Genetic Predisposition to Disease  Primates/genetics  Autism spectrum disorder  Gsea  Genetic constraint  Primate model  Whole genome sequencing  mGAP database protocols adhered to the NIH and the Guide for Use and Care of  Laboratory Animals and were approved by the Oregon Health & Sciences University  Animal Utilization and Care Committee [22]. Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Significant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. METHODS: We used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. RESULTS: We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4 * 10(- 27)). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1 * 10(- 46)), epilepsy (p = 2.1 * 10(- 33)) and schizophrenia (p = 4.2 * 10(- 45)), and for an overlapping neurodevelopmental gene set (p = 4.0 * 10(- 10)). LIMITATIONS: The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. CONCLUSION: The presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions. En ligne : https://dx.doi.org/10.1186/s13229-024-00633-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

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