Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease

Nat Genet. 2002 Oct;32(2):237-44. doi: 10.1038/ng998. Epub 2002 Sep 23.


Genetic studies of Hirschsprung disease, a common congenital malformation, have identified eight genes with mutations that can be associated with this condition. Mutations at individual loci are, however, neither necessary nor sufficient to cause clinical disease. We conducted a genome-wide association study in 43 Mennonite family trios using 2,083 microsatellites and single-nucleotide polymorphisms and a new multipoint linkage disequilibrium method that searches for association arising from common ancestry. We identified susceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, encoding a G protein-coupled receptor (GPCR) and the gene at 10q11 is RET, encoding a receptor tyrosine kinase (RTK). Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and non-complementation of aganglionosis in mouse intercrosses between Ret null and the Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB and RET. Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.

MeSH terms

  • Animals
  • Chromosome Mapping
  • Chromosomes, Human, Pair 10
  • Chromosomes, Human, Pair 13
  • Chromosomes, Human, Pair 16
  • Drosophila Proteins*
  • Epistasis, Genetic*
  • Genetic Markers
  • Hirschsprung Disease / genetics*
  • Hirschsprung Disease / metabolism
  • Hirschsprung Disease / pathology
  • Humans
  • Intestine, Large / pathology
  • Linkage Disequilibrium
  • Lod Score
  • Mice
  • Microsatellite Repeats
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, Endothelin B
  • Receptors, Endothelin / genetics*
  • Receptors, Endothelin / metabolism


  • Drosophila Proteins
  • Genetic Markers
  • Proto-Oncogene Proteins
  • Receptor, Endothelin B
  • Receptors, Endothelin
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, mouse