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To date, genome-wide single nucleotide polymorphism (SNP) and copy number variant (CNV) association studies of autism spectrum disorders (ASDs) have led to promising signals but not to easily interpretable or translatable results. Our own genome-wide association study (GWAS) showed significant association to an intergenic SNP near Semaphorin 5A ( SEMA5A ) and provided evidence for reduced expression of the same gene. In a novel GWAS follow-up approach, we map an expression regulatory pathway for a GWAS candidate gene,  SEMA5A ,  in silico  by using population expression and genotype data sets. We find that the  SEMA5A  regulatory network significantly overlaps rare autism-specific CNVs. The  SEMA5A  regulatory network includes previous autism candidate genes and regions, including  MACROD2 ,  A2BP1 ,  MCPH1 ,  MAST4 ,  CDH8 ,  CADM1 ,  FOXP1 ,  AUTS2 ,  MBD5 , 7q21, 20p,  USH2A ,  KIRREL3 ,  DBF4B  and  RELN , among others. Our results provide: (i) a novel data-derived network implicated in autism, (ii) evidence that the same pathway seeded by an initial SNP association shows association with rare genetic variation in ASDs, (iii) a potential mechanism of action and interpretation for the previous autism candidate genes and genetic variants that fall in this network, and (iv) a novel approach that can be applied to other candidate genes for complex genetic disorders. We take a step towards better understanding of the significance of  SEMA5A  pathways in autism that can guide interpretation of many other genetic results in ASDs.

An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk