Genome-wide association study of Hirschsprung’s disease

Abstract

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 500 K marker set. We genotyped 493,840 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. Aside from SNPs in RET, the strongest overall associations were found for two SNPs on chromosome 8p, yielding odds ratios of 1.68 [CI95%:(1.40,2.00), P = 1.88 9 10–8] and 1.98 [CI95%:(1.59,2.47), P = 6.12 9 10–10], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and the 8p locus (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 8p risk heterozygote. Our highly significant association findings are backedup by the important role of the identified gene as a regulator of the development of the enteric ganglia precursors.