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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

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...

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Autores principales: Hu, Valerie W., Bi, Chongfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689346/
https://www.ncbi.nlm.nih.gov/pubmed/33281715
http://dx.doi.org/10.3389/fneur.2020.578972
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author Hu, Valerie W.
Bi, Chongfeng
author_facet Hu, Valerie W.
Bi, Chongfeng
author_sort Hu, Valerie W.
collection PubMed
description 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.
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spelling pubmed-76893462020-12-04 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. Bi, Chongfeng Front Neurol Neurology 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. Frontiers Media S.A. 2020-11-12 /pmc/articles/PMC7689346/ /pubmed/33281715 http://dx.doi.org/10.3389/fneur.2020.578972 Text en Copyright © 2020 Hu and Bi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Hu, Valerie W.
Bi, Chongfeng
Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes
title Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes
title_full Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes
title_fullStr Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes
title_full_unstemmed Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes
title_short Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes
title_sort phenotypic subtyping and re-analyses of existing transcriptomic data from autistic probands in simplex families reveal differentially expressed and asd trait-associated genes
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689346/
https://www.ncbi.nlm.nih.gov/pubmed/33281715
http://dx.doi.org/10.3389/fneur.2020.578972
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