title: Genome-wide association study identifies NRG1 as a susceptibility locus for 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 500K marker set. We successfully genotyped 293,836 SNPs in 181 Chinese subjects with sporadic HSCR and 346 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 in plausible candidate genes were found for 2 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 x 10(-8)] and 1.98 [CI(95%):(1.59, 2.47), P = 1.12 x 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, indicating that NRG1 is a modifier of HSRC penetrance. 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 an additional HSCR susceptibility locus not only opens unique 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.
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong.
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barcelo
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Thomas Yuk-Yu
authors.initials: TY
authors.lastname: Leon
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Cathy Ka-Yee
authors.initials: CK
authors.lastname: Shum
authors.forename: Feng-Qin
authors.initials: FQ
authors.lastname: Liu
authors.forename: Ming-Yiu
authors.initials: MY
authors.lastname: Yeung
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Sun
authors.forename: Liu-Ming
authors.initials: LM
authors.lastname: Huang
authors.forename: Jin-Fa
authors.initials: JF
authors.lastname: Tou
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Song
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
authors.forename: Kenneth M C
authors.initials: KM
authors.lastname: Cheung
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
mesh_terms: D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020890:Neuregulin-1; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics
chemical_list: D005819:Genetic Markers; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D051096:Proto-Oncogene Proteins c-ret