Lukas S Schaffer, Sophie Breunig, Jeremy M Lawrence, Isabelle F Foote, Andrew D Grotzinger
{"title":"Characterizing genetic pathways unique to autism spectrum disorder at multiple levels of biological analysis.","authors":"Lukas S Schaffer, Sophie Breunig, Jeremy M Lawrence, Isabelle F Foote, Andrew D Grotzinger","doi":"10.1186/s13229-024-00624-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Limitations: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"15 1","pages":"46"},"PeriodicalIF":6.3000,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481320/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Autism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13229-024-00624-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.