Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease

Abstract

Background and objectives: Hirschsprung’s disease (HSCR), or aganglionic megacolon, is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. RET is a well-established susceptibility locus, although existing evidence strongly suggests additional loci contributing to sporadic HSCR. To identify these additional genetic loci, we carried out a genome-wide association study using the Affymetrix 500K marker set. Methods: We genotyped 4 93 840 single-nucleotide polymorphisms (SNPs) in 200 Chinese subjects with sporadic HSCR and 306 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Results: Aside from SNPs in RET, the strongest overall associations were found for two SNPs located in intron 1 of the neuregulin1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68 [CI 95%:(1.40, 2.00), P = 1.80 · 10–8] and 1.98 [CI 95%:(1.59, 2.47), P = 1.12 · 10–9], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and NRG1 (P = 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote. Conclusions: Our highly significant association findings are backed-up by the important role of NRG1 as regulator of the development of the enteric ganglia precursors. The identification of NRG1 as a new HSCR susceptibility locus not only opens new fields of investigation into the mechanisms underlying the HSCR pathology, but also the mechanisms by which a discrete number of loci interact with each other to cause disease.