Association of CDH11 with Autism Spectrum Disorder Revealed by Matched-gene Co-expression Analysis and Mouse Behavioral Studies

Nan Wu,Xiao-Bing Yuan,Yue Wang,Jing-Yan Jia,Yi-Hsuan Pan

doi:10.1007/s12264-021-00770-0

Abstract

A large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features – gene size, mRNA abundance, and guanine-cytosine content – affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD.

Highlights

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a complex genetic basis [1, 2]
The results showed that three gene features – gene size, mRNA abundance, and guanine-cytosine content – affect the genome-wide co-expression profiles of high-confidence ASD risk genes (hcASDs)
The results showed a bell-shaped curve when genes were ranked by mRNA abundance, suggesting that genes with medium expression levels are more likely to be co-expressed with the hcASD gene set (Fig. 2B, left panel)

Summary

Introduction

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a complex genetic basis [1, 2]. A large number of putative risk genes have been identified by genetic linkage analyses, genome-wide association studies, whole-exome sequencing, or wholegenome sequencing [3,4,5]. The functions of most of these putative risk genes in the developing brain remain unknown. For some novel risk genes, the genetic evidence supporting their association with ASD is not sufficient. Causal relationships between the variations of many risk genes and autism traits have not been established. In order to prioritize the investigation of genes and signaling pathways of high relevance to ASD, a method to determine the functional importance of a large group of putative risk genes is vital

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Results

Conclusion