Dataset Information

Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes.

ABSTRACT: Autism spectrum disorder (ASD) describes a collection of neurodevelopmental disorders characterized by core symptoms that include social communication deficits and repetitive, stereotyped behaviors often coupled with restricted interests. Primary challenges to understanding and treating ASD are the genetic and phenotypic heterogeneity of cases that complicates all omics analyses as well as a lack of information on relationships among genes, pathways, and autistic traits. In this study, we re-analyze existing transcriptomic data from simplex families by subtyping individuals with ASD according to multivariate cluster analyses of clinical ADI-R scores that encompass a broad range of behavioral symptoms. We also correlate multiple ASD traits, such as deficits in verbal and non-verbal communication, play and social skills, ritualistic behaviors, and savant skills, with expression profiles using Weighted Gene Correlation Network Analyses (WGCNA). Our results show that subtyping greatly enhances the ability to identify differentially expressed genes involved in specific canonical pathways and biological functions associated with ASD within each phenotypic subgroup. Moreover, using WGCNA, we identify gene modules that correlate significantly with specific ASD traits. Network prediction analyses of the genes in these modules reveal canonical pathways as well as neurological functions and disorders relevant to the pathobiology of ASD. Finally, we compare the WGCNA-derived data on autistic traits in simplex families with analogous data from multiplex families using transcriptomic data from our previous studies. The comparison reveals overlapping trait-associated pathways as well as upstream regulators of the module-associated genes that may serve as useful targets for a precision medicine approach to ASD.

SUBMITTER: Hu VW

PROVIDER: S-EPMC7689346 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes.

Hu Valerie W VW Bi Chongfeng C

Frontiers in neurology 20201112

Autism spectrum disorder (ASD) describes a collection of neurodevelopmental disorders characterized by core symptoms that include social communication deficits and repetitive, stereotyped behaviors often coupled with restricted interests. Primary challenges to understanding and treating ASD are the genetic and phenotypic heterogeneity of cases that complicates all omics analyses as well as a lack of information on relationships among genes, pathways, and autistic traits. In this study, we re-ana ...[more]

PMID: 33281715

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Project description:BACKGROUND:Younger siblings of children with autism spectrum disorder (ASD) are at increased likelihood of receiving an ASD diagnosis and exhibiting other developmental concerns. It is unknown how quantitative variation in ASD traits and broader developmental domains in older siblings with ASD (probands) may inform outcomes in their younger siblings. METHODS:Participants included 385 pairs of toddler siblings and probands from the Infant Brain Imaging Study. ASD probands (mean age 5.5?years, range 1.7 to 15.5?years) were phenotyped using the Autism Diagnostic Interview-Revised (ADI-R), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Siblings were assessed using the ADI-R, VABS-II, Mullen Scales of Early Learning (MSEL), and Autism Diagnostic Observation Schedule (ADOS) and received a clinical best estimate diagnosis at 24?months using DSM-IV-TR criteria (n?=?89 concordant for ASD; n?=?296 discordant). We addressed two aims: (1) to determine whether proband characteristics are predictive of recurrence in siblings and (2) to assess associations between proband traits and sibling dimensional outcomes at 24?months. RESULTS:Regarding recurrence risk, proband SCQ scores were found to significantly predict sibling 24-month diagnostic outcome (OR for a 1-point increase in SCQ?=?1.06; 95% CI?=?1.01, 1.12). Regarding quantitative trait associations, we found no significant correlations in ASD traits among proband-sibling pairs. However, quantitative variation in proband adaptive behavior, communication, and expressive and receptive language was significantly associated with sibling outcomes in the same domains; proband scores explained 9-18% of the variation in cognition and behavior in siblings with ASD. Receptive language was particularly strongly associated in concordant pairs (ICC?=?0.50, p?<?0.001). CONCLUSIONS:Proband ASD symptomology, indexed by the SCQ, is a predictor of familial ASD recurrence risk. While quantitative variation in social communication and restricted and repetitive behavior were not associated among sibling pairs, standardized ratings of proband language and communication explained significant variation in the same domains in the sibling at 24?months, especially among toddlers with an ASD diagnosis. These data suggest that proband characteristics can alert clinicians to areas of developmental concern for young children with familial risk for ASD.

Dataset Information

Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes.

Publications

Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes.

Similar Datasets

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