5 recherche sur le mot-clé 'Polymorphism, Single Nucleotide'

Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder / C. L. YIN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 23p. Titre : Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : C. L. YIN, Auteur ; H. I. CHEN, Auteur ; L. H. LI, Auteur ; Yi-Ling CHIEN, Auteur ; H. M. LIAO, Auteur ; Miao-Churn CHOU, Auteur ; W. J. CHOU, Auteur ; W. C. TSAI, Auteur ; Yen-Nan CHIU, Auteur ; Y. Y. WU, Auteur ; C. Z. LO, Auteur ; J. Y. WU, Auteur ; Y. T. CHEN, Auteur ; S. S. GAU, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Adolescent  Asian Continental Ancestry Group/genetics  Autism Spectrum Disorder/etiology/genetics  Child  China  Cohort Studies  DNA Copy Number Variations  Down-Regulation  Exons  Female  Genome-Wide Association Study  Genotype  Humans  Male  Odds Ratio  Pedigree  Phenotype  Polymorphism, Single Nucleotide  Ubiquitin-Protein Ligases/genetics  Autism spectrum disorder (ASD)  Copy number variations (CNVs)  Family study  Gene expression  Park2 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. METHODS: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). RESULTS: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. CONCLUSIONS: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494754. En ligne : http://dx.doi.org/10.1186/s13229-016-0087-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder [Texte imprimé et/ou numérique] / C. L. YIN, Auteur ; H. I. CHEN, Auteur ; L. H. LI, Auteur ; Yi-Ling CHIEN, Auteur ; H. M. LIAO, Auteur ; Miao-Churn CHOU, Auteur ; W. J. CHOU, Auteur ; W. C. TSAI, Auteur ; Yen-Nan CHIU, Auteur ; Y. Y. WU, Auteur ; C. Z. LO, Auteur ; J. Y. WU, Auteur ; Y. T. CHEN, Auteur ; S. S. GAU, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 23p. Mots-clés : Adolescent  Asian Continental Ancestry Group/genetics  Autism Spectrum Disorder/etiology/genetics  Child  China  Cohort Studies  DNA Copy Number Variations  Down-Regulation  Exons  Female  Genome-Wide Association Study  Genotype  Humans  Male  Odds Ratio  Pedigree  Phenotype  Polymorphism, Single Nucleotide  Ubiquitin-Protein Ligases/genetics  Autism spectrum disorder (ASD)  Copy number variations (CNVs)  Family study  Gene expression  Park2 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. METHODS: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). RESULTS: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. CONCLUSIONS: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494754. En ligne : http://dx.doi.org/10.1186/s13229-016-0087-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder / H. PEYRE in Journal of Child Psychology and Psychiatry, 62-11 (November 2021)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 62-11 (November 2021) . - p.1285-1296 Titre : Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder Type de document : Texte imprimé et/ou numérique Auteurs : H. PEYRE, Auteur ; T. SCHOELER, Auteur ; C. LIU, Auteur ; C. M. WILLIAMS, Auteur ; N. HOERTEL, Auteur ; A. HAVDAHL, Auteur ; J. B. PINGAULT, Auteur Article en page(s) : p.1285-1296 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/epidemiology/genetics  Autism Spectrum Disorder/epidemiology/genetics  Comorbidity  Genome-Wide Association Study  Genomics  Humans  Paired Box Transcription Factors/genetics  Polymorphism, Single Nucleotide  Repressor Proteins/genetics  Autism spectrum disorder  Gwas  Snp  attention deficit hyperactivity disorder  colocalization  common genetic variants  comorbidity  genomic structural equation modelling Index. décimale : PER Périodiques Résumé : BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS: With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS: We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. CONCLUSIONS: Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment. En ligne : http://dx.doi.org/10.1111/jcpp.13479 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=456 [article] Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder [Texte imprimé et/ou numérique] / H. PEYRE, Auteur ; T. SCHOELER, Auteur ; C. LIU, Auteur ; C. M. WILLIAMS, Auteur ; N. HOERTEL, Auteur ; A. HAVDAHL, Auteur ; J. B. PINGAULT, Auteur . - p.1285-1296. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 62-11 (November 2021) . - p.1285-1296 Mots-clés : Attention Deficit Disorder with Hyperactivity/epidemiology/genetics  Autism Spectrum Disorder/epidemiology/genetics  Comorbidity  Genome-Wide Association Study  Genomics  Humans  Paired Box Transcription Factors/genetics  Polymorphism, Single Nucleotide  Repressor Proteins/genetics  Autism spectrum disorder  Gwas  Snp  attention deficit hyperactivity disorder  colocalization  common genetic variants  comorbidity  genomic structural equation modelling Index. décimale : PER Périodiques Résumé : BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS: With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS: We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. CONCLUSIONS: Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment. En ligne : http://dx.doi.org/10.1111/jcpp.13479 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=456

Phenotypic and ancestry-related assortative mating in autism / Jing ZHANG in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 27p. Titre : Phenotypic and ancestry-related assortative mating in autism Type de document : Texte imprimé et/ou numérique Auteurs : Jing ZHANG, Auteur ; J. Dylan WEISSENKAMPEN, Auteur ; Rachel L. KEMBER, Auteur ; iPSYCH CONSORTIUM, Auteur ; Jakob GROVE, Auteur ; Anders D. BØRGLUM, Auteur ; Elise B. ROBINSON, Auteur ; Edward S. BRODKIN, Auteur ; Laura ALMASY, Auteur ; Maja BUCAN, Auteur ; Ronnie SEBRO, Auteur Article en page(s) : 27p. Langues : Anglais (eng) Mots-clés : Humans  Autistic Disorder/genetics  Phenotype  Male  Female  Linkage Disequilibrium  Multifactorial Inheritance  Child  Genetic Predisposition to Disease  Polymorphism, Single Nucleotide  Adult  Intellectual Disability/genetics  Assortative mating  Autism  Genetic ancestry  Intellectual disability  Linkage disequilibrium  Polygenic scores Index. décimale : PER Périodiques Résumé : BACKGROUND: Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population. METHODS: To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families). RESULTS: We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|>?0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D(2) on the order of 1?*?10(-5)). LIMITATIONS: We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification. CONCLUSIONS: This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for En ligne : https://dx.doi.org/10.1186/s13229-024-00605-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Phenotypic and ancestry-related assortative mating in autism [Texte imprimé et/ou numérique] / Jing ZHANG, Auteur ; J. Dylan WEISSENKAMPEN, Auteur ; Rachel L. KEMBER, Auteur ; iPSYCH CONSORTIUM, Auteur ; Jakob GROVE, Auteur ; Anders D. BØRGLUM, Auteur ; Elise B. ROBINSON, Auteur ; Edward S. BRODKIN, Auteur ; Laura ALMASY, Auteur ; Maja BUCAN, Auteur ; Ronnie SEBRO, Auteur . - 27p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 27p. Mots-clés : Humans  Autistic Disorder/genetics  Phenotype  Male  Female  Linkage Disequilibrium  Multifactorial Inheritance  Child  Genetic Predisposition to Disease  Polymorphism, Single Nucleotide  Adult  Intellectual Disability/genetics  Assortative mating  Autism  Genetic ancestry  Intellectual disability  Linkage disequilibrium  Polygenic scores Index. décimale : PER Périodiques Résumé : BACKGROUND: Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population. METHODS: To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families). RESULTS: We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|>?0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D(2) on the order of 1?*?10(-5)). LIMITATIONS: We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification. CONCLUSIONS: This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for En ligne : https://dx.doi.org/10.1186/s13229-024-00605-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

An Association Study of Gamma-Aminobutyric Acid Type A Receptor Variants and Susceptibility to Autism Spectrum Disorders / P. ADAK in Journal of Autism and Developmental Disorders, 51-11 (November 2021)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 51-11 (November 2021) . - p.4043-4053 Titre : An Association Study of Gamma-Aminobutyric Acid Type A Receptor Variants and Susceptibility to Autism Spectrum Disorders Type de document : Texte imprimé et/ou numérique Auteurs : P. ADAK, Auteur ; S. SINHA, Auteur ; N. BANERJEE, Auteur Article en page(s) : p.4043-4053 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Humans  Pilot Projects  Polymorphism, Single Nucleotide  Receptors, GABA  Receptors, GABA-A/genetics  gamma-Aminobutyric Acid  Autism spectrum disorders  Cars  Children  Gabra5  Gabrb3  Gabrg3  Mdr Index. décimale : PER Périodiques Résumé : In this pilot study, we aim to identify the role of few genetic variants of GABA-receptor type A subunits GABRB3 (rs4906902, rs7171660), GABRG3 (rs208129, rs140679), GABRA5 (rs 140681) in the aetiology of autism spectrum disorders in a population of West Bengal. 192 ASD probands, their parents and 184 ethnically-matched healthy controls were recruited for the study. The rs4906902G and the rs140679T conferred significant risk towards ASD. rs7171660 and rs140679 had transmission bias in the family. Neither alleles of rs 208129 and rs 140681 showed significant over-representation in either groups. All these variants were associated with at least one deficit in ASD-associated phenotypes like 'relating to people', 'Imitation', 'emotional response', 'body use', 'taste, smell, touch response' and 'activity levels'. En ligne : http://dx.doi.org/10.1007/s10803-020-04865-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=454 [article] An Association Study of Gamma-Aminobutyric Acid Type A Receptor Variants and Susceptibility to Autism Spectrum Disorders [Texte imprimé et/ou numérique] / P. ADAK, Auteur ; S. SINHA, Auteur ; N. BANERJEE, Auteur . - p.4043-4053. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 51-11 (November 2021) . - p.4043-4053 Mots-clés : Autism Spectrum Disorder/genetics  Humans  Pilot Projects  Polymorphism, Single Nucleotide  Receptors, GABA  Receptors, GABA-A/genetics  gamma-Aminobutyric Acid  Autism spectrum disorders  Cars  Children  Gabra5  Gabrb3  Gabrg3  Mdr Index. décimale : PER Périodiques Résumé : In this pilot study, we aim to identify the role of few genetic variants of GABA-receptor type A subunits GABRB3 (rs4906902, rs7171660), GABRG3 (rs208129, rs140679), GABRA5 (rs 140681) in the aetiology of autism spectrum disorders in a population of West Bengal. 192 ASD probands, their parents and 184 ethnically-matched healthy controls were recruited for the study. The rs4906902G and the rs140679T conferred significant risk towards ASD. rs7171660 and rs140679 had transmission bias in the family. Neither alleles of rs 208129 and rs 140681 showed significant over-representation in either groups. All these variants were associated with at least one deficit in ASD-associated phenotypes like 'relating to people', 'Imitation', 'emotional response', 'body use', 'taste, smell, touch response' and 'activity levels'. En ligne : http://dx.doi.org/10.1007/s10803-020-04865-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=454

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 et/ou numérique 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 et/ou numérique] / 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