To examine if cell-adhesion molecules, as a gene family, associate with ASDs, we applied two pathway-based association approaches on the genotype data (Supplementary Methods). First, we assign each SNP to the overlapping or the closest gene, summarize the significance of each gene using the Simes-adjusted P value42 from its SNPs, and then test whether the distribution of P values differ between a group of genes and all other genes using a nonparametric rank sum test. Using the combined P values from the two discovery cohorts, we found that a group of 25 related cadherin genes show more significant association with ASDs than all other genes (P = 0.02), whereas a stronger enrichment signal (P = 0.004) was obtained when the 25 cadherin genes were combined with eight neurexin family genes (NRXN1 to NRXN3, CNTNAP1 to CNTNAP5). Second, we analysed the ACC cohort using a formal pathway-association method for case-control data sets43. This method examines whether statistics for a group of genes have modest yet consistent deviation from what is expected by chance, through shuffling case/control labels many times, each time
