Gene Network Analysis of Autism and Autoimmue Disorders
Background:”Autism is highly heritable, but the genetic risk factors of autism are still largely unclear and considered to be very heterogeneous. There are several family cohort studies suggesting shared genetic etiology between autism and autoimmune disorders, but detailed comparative studies have not yet been done.In this context, we compared candidate susceptibility gene sets between two groups and verified our findings with postmortem gene expression data.
To identify shared candidate genes between autism and autoimmune disorders and to verify them by differential expression patterns in autism patients’ brain.
We used an autism candidate gene set (717 genes) retrieved from our autism-specific knowledge base, Autworks (http://autworks.hms.harvard.edu), and ten autoimmune disorders including ankylosing spondylitis (AS, 249 genes), autoimmune thyroid disorder (ATD, 227 genes), celiac disorder (CD, 582 genes), inflammatory bowel disorder (IBD, 859 genes), multiple sclerosis (MS, 1463 genes), psoriasis (PS, 829 genes), rheumatoid arthritis (RA, 1814 genes), systemic lupus erythematosus (SLE, 1258 genes), spondylitis (SP, 313 genes), and type I diabetes (T1D, 1575 genes) identified through our cross-disorder knowledge base called Genotator (http://genotator.hms.harvard.edu). For verification, we obtained whole genome, brain tissue expression data of 19 autistic patients and 17 control samples from Gene Expression Omnibus (GSE28521). Networks of candidate risk genes were obtained from STRING database (http://string.embl.de) with a very rigorous confidence score threshold (0.9, max score 0.99).
We identified 294 common risk genes between autism and the set of autoimmune disorders. Thirty of these genes were significantly differentially expressed in the cerebellum of case with autism. These genes include RNA binding proteins (RBFOX1), GABA receptor genes (GABRA1, GABRB3), and MHC specific genes (HLA-A). We also identified 8 possible novel candidate genes for autism, by analyzing autoimmune risk genes that have strong association with known ASD candidate genes and are differentially expressed in the autism patient samples. These genes include heat-shock protein (HSP90AA1), lymphocyte antigen (LY96), and nuclear receptor co-activator gene (NCOA1).
We examined a group of autism candidate genes that may share common genetic risk factors with autoimmune disorders. Of interest, RBFOX1 gene was common in MS and SLE, and RARA gene, which falls in 17q21 region, was common in MS, PS, and T1D. We also identified possible novel autism candidate genes by network analysis including NCOA1 which interacts with RARA and differentially expressed in autistic patient samples. These results reinforce the idea of common genetic pathologies between autism and autoimmune disorders.”