Characteristics and Predictive Value of Blood Transcriptome Signature in Males with Autism Spectrum Disorders
Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases.
Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD.
The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62–0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65–0.82), but not for female samples (AUC 0.51, 95% CI 0.36–0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58–0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.
“Among the significant genes in ASP, only one gene, PTPRE, overlapped with the AUT vs. control or PDDNOS vs. control comparisons while 36 genes were in common between AUT vs. control and PDDNOS vs. control (Fig. S2).”
“In brief, the neurotrophin signaling pathway (KEGG pathway identifier: hsa04722) was the most significant (EASE score P=0.00023, FDR 0.0026) among 22 overrepresented pathways (EASE score P<0.05, corresponding FDR 0.44). The neurotrophin signaling pathway includes neurotrophins and their second messenger systems such as the MAPK pathway, PI3K pathway, and PLC pathway, which have been identified by others ,  as important for neural development, learning and memory, and syndromic ASDs such as tuberous sclerosis and Smith-Lemli-Opitz syndrome.”
Neurotrophin-regulated signalling pathways
Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems.
Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC).
In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-γ1 and signalling pathways controlled through these proteins, such as the MAP kinases.
Activation of p75NTR results in activation of the nuclear factor-κB (NF-κB) and Jun kinase as well as other signalling pathways.
Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation.
The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function.
Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
“Interestingly, long-term potentiation and long-term depression pathways were also significant”
|Autistic Disorder Total Number 104 (P2)||40 (75)||–|
|PDD, NOS||49 (76)||–|
|Asperger’s Disorder||15 (87)|