Association of NRG1 and AUTS2 genetic polymorphisms with Hirschsprung disease in a South Chinese population

J Cell Mol Med. 2018 Apr;22(4):2190-2199. doi: 10.1111/jcmm.13498. Epub 2018 Jan 29.


Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of enteric ganglia. There are more than 15 genes identified as contributed to HSCR by family-based or population-based approaches. However, these findings were not fulfilled to explain the heritability of most sporadic cases. In this study, using 1470 HSCR and 1473 control subjects in South Chinese population, we replicated two variants in NRG1 (rs16879552, P = 1.05E-04 and rs7835688, P = 1.19E-07), and further clarified the two replicated SNPs were more essential for patients with short-segment aganglionosis (SHSCR) (P = 2.37E-05). We also tried to replicate the most prominent signal (rs7785360) in AUTS2, which was a potential susceptibility gene with HSCR. In our results, in terms of individual association, marginal effect was observed to affect the HSCR patients following recessive model (P = 0.089). Noteworthy, significant intergenic synergistic effect between rs16879552 (NRG1) and rs7785360 (AUTS2) was identified through cross-validation by logistic regression (P = 2.45E-03, OR = 1.53) and multifactor dimensionality reduction (MDR, P < 0.0001, OR = 1.77). Significant correlation was observed between expression of these two genes in the normal segments of the colons (P = 0.018), together with differential expression of these genes between aganglionic colonic segments and normal colonic segments of the HSCR patients (P value for AUTS2 <0.0001, P value for NRG1 = 0.0243). Although functional evaluation is required, we supply new evidence for the NRG1 to HSCR and raised up a new susceptibility gene AUTS2 to a specific symptom for the disease.

Keywords: Hirschsprung disease; association; epistasis; subclinical stratification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian People / genetics*
  • Case-Control Studies
  • Colon / pathology
  • Cytoskeletal Proteins
  • DNA, Intergenic / genetics
  • Epistasis, Genetic
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Hirschsprung Disease / genetics*
  • Humans
  • Logistic Models
  • Multifactor Dimensionality Reduction
  • Neuregulin-1 / genetics*
  • Organ Specificity / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Proteins / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Transcription Factors


  • AUTS2 protein, human
  • Cytoskeletal Proteins
  • DNA, Intergenic
  • NRG1 protein, human
  • Neuregulin-1
  • Proteins
  • RNA, Messenger
  • Transcription Factors