Use of Blood Transcriptomes to Characterize ASD Phenotypes

Thursday, May 14, 2015: 5:30 PM-7:00 PM
Imperial Ballroom (Grand America Hotel)
B. Stamova1, Y. Tian1, C. W. Nordahl2, M. D. Shen2, S. J. Rogers2, D. G. Amaral2 and F. R. Sharp3, (1)MIND Institute and Department of Neurology, University of California Davis Medical Center, Sacramento, CA, (2)MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, CA, (3)Department of Neurology, University of California, Davis, School of Medicine, Sacramento, CA
Background: RNA expression differences have been reported in autism spectrum disorders (ASD) for blood and brain. Significantly for the present study, a recent investigation of ASD brain found that some genes displayed differential alternative splicing (DAS) of targets of the splicing factor A2BP1. This data and the fact that DAS is implicated in a number of neuropsychiatric disorders led us to consider to following aims.


  • To determine if there is DAS in blood mRNA in: a) ASD subjects compared to typically developing (TD) controls; and b) ASD subgroups related to total cerebral volume (TCV), since abnormal brain enlargement is one of the most consistent findings in the neuropathology of a subset of ASD.
  • To develop a method, which addresses ASD heterogeneity at transcriptome level and can identify subgroups of ASD with common affected pathways. This can be instrumental in identifying candidates for specific pharmacological treatments, and in associating these pathways with specific clinical or molecular phenotypes.

Methods: RNA from blood was processed on whole genome exon arrays for 2-4 year old ASD and TD boys. Mixed Effects Regression Models were used to predict DAS for all ASD (n=30), ASD with normal TCV, and ASD with large TCV compared to TD controls (n=20) (FDR p<0.05).

Results: A specific DAS signature was observed for All ASD, and distinct DAS was observed for the TCV-based ASD subgroups. A number of genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS were involved in pathways implicated in previous ASD studies, such as Natural Killer Cell, mTOR, and NGF signaling. However, this was the first study to suggest DAS occurred in these pathways. To address ASD heterogeneity and identify convergent pathways in ASD subgroups, we performed sub-analysis at the level of each individual ASD subject. A variety of different combinations of pathways appeared to be associated with idiopathic ASD. This would be consistent with many genetic and/or environmental causes of ASD which are also associated with many different pathways. However, it also showed convergence on similar biological processes at least for subgroups of ASD subjects. Notably, 60% of ASD subjects in this study had DAS abnormalities of mTOR signaling, of significance since single-gene disorders often associated with ASD clinical features also had aberrant mTOR signaling including Fragile X, tuberous sclerosis, PTEN, and neurofibromatosis. Thus these data point to possible abnormalities of mTOR pathways in a subgroup of ‘idiopathic’ ASD which may have clinical relevance since mTOR inhibitors, like rapamycin can modulate these pathways.

Conclusions: This study suggests DAS occurs in blood of 2-4-year old boys with ASD compared to TD controls. ASD subgroups based on TCV exhibited distinct DAS, suggesting they may have different biological underpinnings. It is likely that many of these changes reflect differences in the ASD peripheral immune system and may be associated with the immune and autoimmune dysregulation observed in some ASD subjects.

See more of: Genetics
See more of: Genetics