Fine Mapping of the NRG1 Hirschsprung's Disease Locus

作者：Clara Sze-Man Tang, Wai-Kiu Tang, Man-Ting So, Xiaoping Miao, Brian Man-Chun Leung, Benjamin Hon Kei Yip, Thomas Yuk-Yu Leon, Esw Ngan, Vincent Chi‐Hang Lui, Yan Chen, Ivy Hau-Yee Chan, Bhy Chung, Xue-Lai Liu, Xuan-Zhao Wu, Kenneth Kak‐Yuen Wong, Pak C. Sham, Stacey S. Cherny, Paul Kwong-Hang Tam, Maria‐Mercè Garcia‐Barceló · 发表于：PLoS ONE · 年份：2011 · DOI：10.1371/journal.pone.0016181 · 被引用次数：52 · 研究领域：Congenital gastrointestinal and neural anomalies、Digestive system and related health、Gastrointestinal disorders and treatments

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 like...