Genetic variants on NRG1 confer susceptibility to Hirschsprung's disease

Abstract

Hirschsprung's disease (HSCR, aganglionic megacolon), is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. Besides the major HSCR gene, RET, and other implicating genes (e.g. EDNRB), existing evidence suggests that additional loci contributing to sporadic HSCR exist. To identify these loci, we conducted a genome-wide association study on 200 Chinese HSCR patients and 408 ethnically matched controls. Apart from SNPs in RET, the strongest overall associations were found for two SNPs (rs16879552 and rs7835688) located in intron 1 of the neuregulin1 gene (NRG1) on 8p12. Replication was carried out on an independent set of 190 HSCR case and 510 control subjects, yielding the combined odds ratios of 1.68 (p=1.80x10-8) and 1.98 (p=1.12x10-9) for the heterozygous risk genotypes of rs16879552 and rs7835688 respectively under the additive model. Significant interaction was also found between RET and NRG1 (p=0.0095), which further increased the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote. The significant association suggests an important role of NRG1 as regulator of the development of the enteric ganglia precursors.