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

Hum Mol Genet. 2013 Jul 15;22(14):2960-72. doi: 10.1093/hmg/ddt150. Epub 2013 Apr 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child Development Disorders, Pervasive / genetics*
  • Chromosome Mapping
  • DNA Copy Number Variations
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease
  • Humans
  • Membrane Proteins / genetics*
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Reelin Protein
  • Risk Factors
  • Semaphorins


  • Membrane Proteins
  • Nerve Tissue Proteins
  • Reelin Protein
  • SEMA5A protein, human
  • Semaphorins
  • RELN protein, human