Human Cerebellar Expression of Autism Associated Genes (P13-9.011)

Abstract

<h3>Objective:</h3> To examine human cerebellar transcriptome of autism associated genes for insights into shared biological processes. <h3>Background:</h3> Cerebellum dysfunction is known to be involved in autism pathophysiology. Autism relevant single-gene assays like for TSC1 have shown a high expression of the gene in the cerebellum. Here we asked if this finding extends to 205 autism associated genes and if high or low expression in the cerebellum was statistically associated with specific subregions and biochemical processes. <h3>Design/Methods:</h3> We examined human brain RNA microarray data made available by Allen Brain Atlas. Data from 169 brain regions including the cerebellum, from 6 human subjects was downloaded for each of 205 autism linked genes in the SFARI database (Category 1 - high confidence genes). Gene set enrichment analysis was done using EnrichR. <h3>Results:</h3> TSC1 expression was significantly high for lobules and Crus I and Crus II but not for deep cerebellar nuclei. For 205 autism-associated genes there was a spectrum of expression, without clustering of genes towards high or low expression. The top one-third of high-expressing genes were associated with processes within the nucleus (adjusted-p&lt;0.0001), and with histone methylase/demethylase (adjusted-p &lt;0.00001). In contrast, the lowest one-third expressing genes were associated with processes linked to glutamatergic synapses (adjusted-p&lt;0.01), and voltage-gated cation channels (adjusted-p&lt;0.001). A deficit of the top one-third expressing genes was associated uniquely with grooming behaviour in animal models (adjusted-p&lt;0.0001) whereas the bottom one-third were associated with motor coordination difficulties in animals models with gene deficits (adjusted-p&lt;0.0001). <h3>Conclusions:</h3> Some, but not all autism linked genes had high expression in the cerebellum, but not in deep cerebellar nuclei. High expressing genes were associated with roles in the nucleus, specifically with histone methylation/demethylation processes indicating their role in regulating DNA expression and plasticity. <b>Disclosure:</b> Dr. Balasubramaniam has nothing to disclose. The institution of Dr. Tsai has received research support from once upon a time foundation. Dr. Jakkamsetti has nothing to disclose.