All significant over-represented canonical pathways associated with module genes corresponding to verbal, non-verbal, social, and all (combined) traits in the simplex population.

Click here for additional data file.^{(59K, xlsx)}

Supplementary Table 9

All significant over-represented canonical pathways associated with module genes corresponding to verbal, non-verbal, play, insistence on sameness, savant, and all (combined) traits in the multiplex population.

Click here for additional data file.^{(111K, xlsx)}

Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Edited by: Lidia V. Gabis, Sheba Medical Center, Israel

Reviewed by: Mariangela Gulisano, University of Catania, Italy; Francesca Felicia Operto, University of Salerno, Italy

*Correspondence: Valerie W. Hu ude.uwg@uhlav

This article was submitted to Pediatric Neurology, a section of the journal Frontiers in Neurology

Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Edited by: Lidia V. Gabis, Sheba Medical Center, Israel

Reviewed by: Mariangela Gulisano, University of Catania, Italy; Francesca Felicia Operto, University of Salerno, Italy

Received 2020 Jul 1; Accepted 2020 Oct 21.

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.

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.

Keywords: ASD subgroups, transcriptomic analysis, simplex families, ASD trait-associated genes, comparison with multiplex population

Abstract

Acknowledgments

We are grateful to both the SSC and AGRE for ADI-R scoresheets from individuals with ASD in both the simplex and multiplex families, respectively, as well as to the families who have generously allowed this information to be publicly available for research.

Acknowledgments

Click here for additional data file.^{(13K, docx)}Click here for additional data file.^{(14K, docx)}Click here for additional data file.^{(38K, xlsx)}Click here for additional data file.^{(27K, xlsx)}Click here for additional data file.^{(24K, xlsx)}Click here for additional data file.^{(26K, xlsx)}Click here for additional data file.^{(20K, xlsx)}Click here for additional data file.^{(59K, xlsx)}Click here for additional data file.^{(111K, xlsx)}

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