Identification of methylation markers for diagnosis of autism spectrum disorder.

Bei Zhang,Yongkang Ni,Xiaoyuan Hu,Lin Xue,Yuefei Li

doi:10.1007/s11011-021-00805-5

Abstract

Autism spectrum disorder (ASD) is a hereditary heterogeneous neurodevelopmental disorder characterized by social and speech dysplasia. We collected the expression profiles of ASD in GSE26415, GSE42133 and GSE123302 from the gene expression omnibus (GEO) database, as well as methylation data of GSE109905. Differentially expressed genes (DEGs) between ASD and controls were obtained by differential expression analysis. Enrichment analysis identified the biological functions and signaling pathways involved by common genes in three groups of DEGs. Protein-protein interaction (PPI) networks were used to identify genes with the highest connectivity as key genes. In addition, we identified methylation markers by associating differentially methylated positions. Key methylation markers were identified using the least absolute shrink and selection operator (LASSO) model. Receiver operating characteristic curves and nomograms were used to identify the diagnostic role of key methylation markers for ASD. A total of 57 common genes were identified in the three groups of DEGs. These genes were mainly enriched in Sphingolipid metabolism and PPAR signaling pathway. In the PPI network, we identified seven key genes with higher connectivity, and used qRT-PCR experiments to verify the expressions. In addition, we identified 31 methylation markers and screened 3 key methylation markers (RUNX2, IMMP2L and MDM2) by LASSO model. Their methylation levels were closely related to the diagnostic effects of ASD. Our analysis identified RUNX2, IMMP2L and MDM2 as possible diagnostic markers for ASD. Identifying different biomarkers and risk genes will contribute to the diagnosis of ASD and the development of new clinical and drug treatments.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide range of barriers from childhood, involving mutual social communication and limited, repetitive interests and behaviors (Murphy et al, 2016)
To identify differentially expressed genes associated with ASD, we performed a differential analysis of gene expression between ASD patients and controls in GSE26415, GSE42133, and GSE123302 (Figure 1A)
Enrichment analysis for 57 common genes revealed that genes were enriched to 162 biological processes (BP), 26 cellular components (CC) and 48 molecular functions (MF)

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide range of barriers from childhood, involving mutual social communication and limited, repetitive interests and behaviors (Murphy et al, 2016). In studies combining brain tissue from adolescents and adults with ASD, transcriptional expression patterns suggested that abnormalities in cortical patterns, synapses, apoptosis, immunity, and inflammation may be associated with autism (Chow et al, 2012). ASD studies showed differential expression of autism candidate genes in lymphoid cell lines of autistic patients (Hu, Frank, Heine, Lee, & Quackenbush, 2006). Another ASD study identified abnormal gene expression patterns in the brains of autistic patients through genome-wide analysis of mRNA levels and CNVs (Chow et al, 2012)

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Conclusion