Genome and Transcriptome Analyses of Induced Pluripotent Stem Cells in ASD

Background: Increased brain size and larger head circumference (macrocephaly) characterizes as many as 20% of children with autism spectrum disorders and confers poorer outcome.

Objectives: To understand the neurobiology of ASD, we derived induced pluripotent stem cells (iPSCs) from 5 children with ASD and macrocephaly and their unaffected family members.

Methods:  IPSCs are pluripotent cells that can be differentiated into any other cell of the body, including neurons. Because iPSCs and their progeny maintain the genetic characteristics of the individual of origin, these cells represent a promising model for diagnostics, drug discovery, therapeutics and personalized medicine.

Results:  Our dataset currently comprises 45 iPSC lines obtained from 15 individuals in 5 families. We analyzed the genomes, transcriptomes, and biological characteristics of iPSCs, neuronal progenitors and neurons of patients with autism spectrum disorder and macrocephaly and their unaffected family members. Using EdgeR and a generalized linear model to account for family differences we found that that probands’ neuronal progenitors and neurons differ from unaffected family members with respect to biofunctions mostly related to Cell cycle/Cell proliferation and Embryonic Development. Indeed, using assays for cell proliferation and differentiation we found that cells from probands have significantly shorter cell cycle, i.e., faster cell division and increased number of proliferative neuronal precursors as compared to unaffected controls.  Furthermore, these neural precursor cells derived from probands with ASD generate significantly more inhibitory GABAergic neurons, while the generation of excitatory neurons is not significantly changed.

Conclusions:  These results suggest an imbalance in excitation and inhibition in early brain development in ASD.  We are currently investigating whether differentially expressed genes are significantly enriched in structural and sequence DNA variation in probands. We conclude that hiPSCs can be useful as a model to elucidate the neurobiological basis of neuropsychiatric disorders of unclear etiology.