title: Fine mapping of the NRG1 Hirschsprung's disease locus.
abstract: The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR.
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, China.
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.forename: Wai-Kiu
authors.initials: WK
authors.lastname: Tang
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Brian Man-Chun
authors.initials: BM
authors.lastname: Leung
authors.forename: Benjamin Hon-Kei
authors.initials: BH
authors.lastname: Yip
authors.forename: Thomas Yuk-Yu
authors.initials: TY
authors.lastname: Leon
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: Ivy Hau-Yee
authors.initials: IH
authors.lastname: Chan
authors.forename: Patrick Ho-Yu
authors.initials: PH
authors.lastname: Chung
authors.forename: Xue-Lai
authors.initials: XL
authors.lastname: Liu
authors.forename: Xuan-Zhao
authors.initials: XZ
authors.lastname: Wu
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D057890:Epigenomics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1