Association ofCDH11with ASD revealed by matched-gene co-expression analysis and mouse behavioral studies

Abstract

Genetic variants of a large group of susceptibility genes have been associated with similar clinical manifestations of autism spectrum disorders (ASD), suggesting convergent function of these genes during brain development. Gene co-expression analysis has emerged as an important tool to identify convergent molecular pathways shared by ASD risk genes. In this study, four gene features, including gene size, mRNA length, mRNA abundance, and guanine-cytosine content, were found to profoundly affect gene co-expression. A new method termed "matched-gene coexpression analysis" (MGCA) was developed to screen for biologically meaningful gene coexpression relationships, taking into the consideration of the effect of these features on gene coexpression. With this method, significant convergence of the expression of high-confidence ASD risk genes (hcASDs) in the brain was demonstrated, and an improved efficacy in the prediction of convergent molecular pathways was achieved. This method also allowed the identification of " homophilic cell adhesion" as one of the convergent pathways of ASD-relevant genes. Analyses of CDH11 and CDH9, two specific genes coding for homophilic cell adhesion molecules, revealed that CDH11, but not CDH9, was significantly co-expressed with hcASDs. In addition, Cdh11-null mice, but not Cdh9-null mice, were found to exhibit multiple autistic-like behavioral alterations.These results suggest that CDH11 is an important ASD risk gene. Results of this study also highlight the importance of considering matched gene features in the analysis of gene coexpression.Conventionally, genome-wide gene co-expression networks are constructed after setting an empirically determined threshold of CC 6 . A major limitation in most of these studies is lack of consideration of effects of confounding factors such as the size, expression level (mRNA abundance), and guanine-cytosine (GC) content of genes on the result of gene co-expression analysis (GCA) 11 . Most hcASDs are large genes with a higher expression level in the brain than in other tissues 12 . It is unclear whether the size or expression level of genes affect the result of GCA. It is also unknown whether convergent expression is specific to ASD risk genes or a common property of genes with similar features, such as large gene size and high mRNA abundance 11 . Some hcASDs code for adhesion molecules, such as members of neurexin and neuroligin families, which mediate pre-and post-synaptic adhesion, respectively, in ASD-related brain circuits 13,14 . Genetic variants of several other adhesion molecules, including classical and nonclassical cadherin family members, are also frequently found to be associated with ASD by GWAS 15 and WES studies [16][17][18][19] . Cadherin family members play important roles in multiple developmental processes, including cell proliferation, polarization, neuronal migration, axon projection, dendrite arborization, and synapse assembly, by mediating homophilic and heterophilic cell-cell interactions [20][21][22][23][24] . It is unclear as...

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