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.

已经报道了大量自闭症谱系障碍（ASD）的推定风险基因。大多数这些易感基因在大脑发育中的功能仍然未知，它们的变异与自闭症特征之间的因果关系尚未确定。本研究的目的是基于与一组高置信度 ASD 风险基因 (hcASD) 的基因共表达分析，在全基因组水平上预测推定的风险基因。结果表明，三个基因特征——基因大小、mRNA丰度和鸟嘌呤-胞嘧啶含量——影响hcASD的全基因组共表达谱。为了规避这些特征在基因共表达分析中的干扰，我们开发了一种方法，通过统计比较该基因与 hcASD 的共表达谱与该基因与特征匹配基因的置换基因集的共表达谱来确定基因是否与 hcASD 显着共表达。这种方法被称为“匹配基因共表达分析”（MGCA）。通过 MGCA，我们证明了 hcASD 发育表达谱的收敛性，并提高了风险基因预测的功效。最近报道的两个 ASD 候选基因的分析结果，CDH11和CDH9表明CDH11而非CDH9参与 ASD。与这一预测一致，行为研究表明，Cdh11缺失小鼠，而不是Cdh9缺失小鼠，具有多种类似自闭症的行为改变。这项研究强调了 MGCA 在揭示 ASD 相关基因方面的能力以及 CDH11 在 ASD 中的潜在作用。