Multiple, independent, common variants at RET, SEMA3 and NRG1 gut enhancers specify Hirschsprung disease risk in European ancestry subjects

Genetic study of 583 European ancestry Hirschsprung disease patients identifies 38 common variants in gut enhancer regions at RET, SEMA3, and NRG1 loci that independently contribute to disease risk. Disease risk increases over 25-fold based on cumulative number of risk alleles, suggesting reduced gene expression across multiple ENS genes integrates through developmental regulatory networks to cause congenital aganglionosis.