Genetics Research
Autism is clearly a heritable disorder, making genetics an essential component of an ACE. Past genetics research on autism has not made fundamental and replicable discoveries largely because the approach has been to conduct large genome-wide searches. Based on our published and pilot research as well as on recent studies by other groups, we hypothesize that very early brain maldevelopment in autism involves regional brain overgrowth.
To identify genes that may underlie brain overgrowth abnormality in autism, we will analyze relationships between brain growth abnormalities and Wnt, neurogenesis, and apoptosis genes and pathways. To discover still other genes that could also be involved in brain overgrowth in autism, we will additionally analyze brain tissue gene expression from autism postmortem cases, and we will also analyze blood-based gene expression in the living study subjects. To separately and additionally test for possible usefulness as a clinical biomarker of autism, we will analyze the relationship between age-related changes in abnormal blood gene expression in at-risk infants between 12 and 36 months and clinical characteristics, including treatment responsiveness. Through these specific and targeted brain-gene analyses, we will be able to identify autism brain growth oversusceptibility genes. Then, to investigate the functional significance of such candidate autism brain overgrowth susceptibility genes, we will model their effects on the growth and differentiation of neural stem cells.
We will pursue several opportunities for exploratory studies. We will generate a wealth of pheotypic data as will the MRI, fMRI, and blood gene expression projects. We will use novel methodology for identifying discrete biobehavioral clusters within our ASD group as well as seeking evidence of corresposnding differences in gene profiles. Further, examining age-related effects in blood gene expression and in brain gene expression presents a unique opportunity for generating hypotheses about ongoing genetic effects in the autistic child. Our preliminary gene expression studies of dorsolateral frontal cortex in postmortem cases of autism raise the possibility that, in addition to gene expression abnormalities that may reflect overgrowth processes, we may detect signs of other aberrant processes as well. Also, analyses of the functional role of selected overgrowth susceptibility genes will almost certainly reveal additional genes and pathways affecting and being affected by targeted brain overgrowth.