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Open AccessArticle

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Department of Biochemistry and Molecular Medicine, The George Washington University, School of Medicine and Health Sciences, Washington, DC 20037, USA
*
Author to whom correspondence should be addressed.
Current address: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Int. J. Mol. Sci. 2020, 21(18), 6877; https://doi.org/10.3390/ijms21186877
Received: 25 August 2020 / Revised: 14 September 2020 / Accepted: 17 September 2020 / Published: 19 September 2020
Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with core deficits in social communication and manifestation of restricted, repetitive, and stereotyped behaviors. Despite the core symptomatology, ASD is extremely heterogeneous with respect to the severity of symptoms and behaviors. This heterogeneity presents an inherent challenge to all large-scale genome-wide omics analyses. In the present study, we address this heterogeneity by stratifying ASD probands from simplex families according to the severity of behavioral scores on the Autism Diagnostic Interview-Revised diagnostic instrument, followed by re-analysis of existing DNA methylation data from individuals in three ASD subphenotypes in comparison to that of their respective unaffected siblings. We demonstrate that subphenotyping of cases enables the identification of over 1.6 times the number of statistically significant differentially methylated regions (DMR) and DMR-associated genes (DAGs) between cases and controls, compared to that identified when all cases are combined. Our analyses also reveal ASD-related neurological functions and comorbidities that are enriched among DAGs in each phenotypic subgroup but not in the combined case group. Moreover, relational gene networks constructed with the DAGs reveal signaling pathways associated with specific functions and comorbidities. In addition, a network comprised of DAGs shared among all ASD subgroups and the combined case group is enriched in genes involved in inflammatory responses, suggesting that neuroinflammation may be a common theme underlying core features of ASD. These findings demonstrate the value of phenotype definition in methylomic analyses of ASD and may aid in the development of subtype-directed diagnostics and therapeutics. View Full-Text
Keywords: phenotypic subgroups stratified by ASD severity; simplex families; DNA methylation; subgroup-associated genes and biological functions phenotypic subgroups stratified by ASD severity; simplex families; DNA methylation; subgroup-associated genes and biological functions
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MDPI and ACS Style

Lee, E.C.; Hu, V.W. Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions. Int. J. Mol. Sci. 2020, 21, 6877. https://doi.org/10.3390/ijms21186877

AMA Style

Lee EC, Hu VW. Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions. International Journal of Molecular Sciences. 2020; 21(18):6877. https://doi.org/10.3390/ijms21186877

Chicago/Turabian Style

Lee, Elizabeth C.; Hu, Valerie W. 2020. "Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions" Int. J. Mol. Sci. 21, no. 18: 6877. https://doi.org/10.3390/ijms21186877

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