Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
Background: Numerous susceptibility genes and chromosomal abnormalities have been associated with autism spectrum disorders (ASD), but most discoveries either fail to be replicated or account for a small effect. Inconclusive results could in part be a reflection of heterogeneous phenotype and indicate the need to employ strategies that identify more homogeneous groups of ASD subjects. Autism might be accompanied with other symptoms. These associated symptoms have been used in subject stratification for linkage and association studies resulting in valuable discoveries. Herein, the central point of our model is based on the concept that obesity might be a co-occurring condition in autism. Recently, there have been suggestive reports for a higher rate of obesity in autism. Overall, there is a paucity of data describing the prevalence of obesity in autism and the limited number of studies conducted did not include medication history. It is not clear if the suggested higher rate of obesity is related to psychotropic medication side effects or to the disorder itself. However, in-depth literatures search suggests that indeed some scientific merit can be found that backs up the potential link between autism and obesity; one such scenario can be found for the mTOR pathway. Implications in the mTOR pathway (composed of two complexes called mTORC1 and mTORC2) have been independently associated with autism and obesity. It has also been reported that rapamycin administration, an inhibitor of mTORC1, will improve autistic-like behaviors observed in mice models for two mTOR genes (Pten and Tsc). These lines of evidence prompted us to systematically evaluate the potential role of mTOR in relation to autistic subjects’ obesity status.
Objectives: To assess the possible relationship between autism and obesity, we evaluated the expression level of mTOR-related genes in autistic subjects with and without obesity.
Methods: Subjects were ascertained from the Autism Genetics Resource Exchange (AGRE). Obesity status was determined using Body Mass Index percentiles. PCR arrays, including the mTOR genes, were conducted on lymphoblastoid cell line-derived RNA from 16 AGRE subjects.
Results: Despite the small sample size in this pilot study, differential expression was detected for several mTOR-related genes in autism-obese group compared with autism-non obese group. Interestingly, two genes with reported connections to both autism and fat metabolism, i.e. EIF4E and PIK3CG, were seen among the differentially expressed genes in the obese group.
Conclusions: This is the first targeted research study to evaluate the expression level of mTOR-related genes taking into consideration the obesity status of autistic subjects. Our pilot study demonstrates that autistic subjects with obesity may represent a more homogeneous subset of this highly heterogeneous population. Applying such a stratification method may provide a way to better understand underlying genetic mechanism in a subset of autistic subjects with a co-occurring obesity. Our study introduces a novel, practical, and effective method to connect different lines of phenotypic and genomic data in unraveling the etiology of this highly heterogeneous neurodevelopmental disorder.