Characterising the transcriptome in autism spectrum disorder using RNAseq

Autism spectrum disorder (ASD) is a common developmental disorder typified by deficits in social communication and stereotyped behaviours. Despite significant progress in identifying genetic risk variants, there is currently... [ view full abstract ]

Autism spectrum disorder (ASD) is a common developmental disorder typified by deficits in social communication and stereotyped behaviours. Despite significant progress in identifying genetic risk variants, there is currently no unified pathomechanistic explanation. Monozygotic (MZ) twins show incomplete concordance in autistic traits, which suggests that alternative risk pathways involving non-shared environmental (NSE) factors could also have an important role to play. 

In this study we performed RNA sequencing of whole blood and characterised genome-wide gene expression in a sample of 23 ASD MZ twin pairs that were concordant for ASD (N= 6 pairs), discordant for ASD (N= 6) and concordant unaffected controls (N=11). We firstly compared ASD affected with unaffected, age-matched controls across the sample (between-group comparison) in order to identify genes and pathways commonly disrupted in ASD. Secondly, we performed within-group and within-pair analyses of the discordant twin pairs in order to identify genes and pathways disrupted by environmental factors.

As expected, fold changes were modest but we identified a number of genes that were differentially expressed (FDR <0.2) in both the between group analysis (DEPDC1B, IGHG4 and ZNF501) and within group analysis (IGHG4, EVI2A, SNORD15B, RGS18, LPAR6 and RPL9).  Geneset testing using  ROAST and ROMER methods found no evidence for enrichment of previously identified ASD risk genes, but identified a number of potentially relevant MSigDB pathways (p < 0.05), including those related to transcriptional control, immune system function and cellular signaling. While none of the genes identified in this study are have been previously established as ASD susceptibility genes, immune system disruption is one of the most consistent findings in transcriptome studies of ASD. Replicating the immune-related genes identified here for further study in larger discordant twin cohorts is a research priority, where we then might begin to investigate links to environmental exposures.