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.