Identification of aberrant innate and adaptive immunity based on changes in global gene expression in the blood of adults with autism spectrum disorder

Abstract

Background Autism spectrum disorder (ASD) is characterized as a neurodevelopmental disorder, and one of the main hypotheses regarding its cause is genetic factors. A previous meta-analysis of seven microarray studies and one RNA sequencing (RNA-seq) study using the blood of children with ASD identified dysregulation of gene expressions relevant to the immune system. In this study, we explored changes in global gene expression as the phenotype of ASD in the blood of adults with ASD. Methods We recruited an RNA-seq cohort (ASD vs. control; n = 6 each) and a replication cohort (ASD vs. control; n = 19 each) and conducted RNA-seq to explore changes in global gene expression. We then subjected the significantly up- and downregulated genes to gene ontology (GO) and core analyses. Weighted gene correlation network analysis (WGCNA) was performed with all 11,617 genes detected in RNA-seq to identify the ASD-specific gene network. Results In total, 117 significantly up- and 83 significantly downregulated genes were detected in the ASD compared with the control group, respectively (p < 0.05 and q < 0.05). GO analysis revealed that the aberrant innate and adaptive immunity were more obvious in the 117 upregulated than in the 83 downregulated genes. WGCNA with core analysis revealed that one module including many immune-related genes was associated with the natural killer cell signaling pathway. In the results for the replication cohort, significant changes with same trend found in RNA-seq data were confirmed for MAFB (p = 0.046), RPSAP58 (p = 0.030), and G2MK (p = 0.004). Limitations The sample size was relatively small in both the RNA-seq and replication cohorts. This study examined the mRNA expression level, so the interaction between mRNA and protein remains unclear. The expression changes between children and adults with ASD were not compared because only adults with ASD were targeted. Conclusions The dysregulated gene expressions confirmed in the blood of adults with ASD were relevant to the dysfunction of innate and adaptive immunity. These findings may aid in understanding the pathogenesis of ASD.

Blood RNA Sequencing Confirms Upregulated BATF2 and FCGR1A Expression in Children with Autism Spectrum Disorder

“…The upregulated expression levels of both BATF2 and FCGR1A in our Israeli cohort of whole blood samples from children with ASD (Fig. 1) corroborate ndings from a recent Japanese RNA-seq study in whole blood from adults with ASD 17 . To our knowledge our study provides the rst validation of a genome-wide RNA-seq study with ASD blood samples.…”

“…A recent RNA-seq study of whole blood from adults with ASD found dysregulated transcription of genes implicated in innate and adaptive immunity. These included upregulated expression of BATF2 and FCGR1A 17 , as con rmed in our current study of whole blood from children with ASD. The consequences to the immune system, of dysregulation in children with ASD of the four genes observed in our study (Fig.…”

“…Our RNA-seq detected SERPING1 as the top upregulated gene in whole blood from children with ASD (FD=3.4962; P adj =0.0072; Table 2). SERPING1 was among the upregulated genes in whole blood from Japanese adults with ASD 17 . Yet, our real-time PCR experiments could not validate this nding in the entire whole blood samples (Supplementary Fig.…”

“…Therefore, our current study appears to be the rst validation of any dysregulated gene in blood samples from individuals diagnosed with ASD. Moreover, our validation was done on children with ASD (Table 1), in contrast to adults with ASD in the mentioned Japanese study 17 .…”

Neuroimmune transcriptome changes in brains of psychiatric and neurological disorder patients

“…Patients with these brain diseases share deficits in cognition, blunted mood, restricted sociability and abnormal behavior to various degrees. Transcriptome studies have identified expression alterations of immune-related genes (IRGs) in postmortem brains of AD( 7 ), PD( 8 ), ASD( 9 ), SCZ( 10-14 ) and BD( 10 ) separately. Cross-disorder transcriptomic studies further highlighted changes in IRGs( 15, 16 ).…”