Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease.
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.
Garcia-Barcelo
Maria-Mercè
MM
Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong.
Tang
Clara Sze-Man
CS
Ngan
Elly Sau-Wai
ES
Lui
Vincent Chi-Hang
VC
Chen
Yan
Y
So
Man-Ting
MT
Leon
Thomas Yuk-Yu
TY
Miao
Xiao-Ping
XP
Shum
Cathy Ka-Yee
CK
Liu
Feng-Qin
FQ
Yeung
Ming-Yiu
MY
Yuan
Zhen-Wei
ZW
Guo
Wei-Hong
WH
Liu
Lei
L
Sun
Xiao-Bing
XB
Huang
Liu-Ming
LM
Tou
Jin-Fa
JF
Song
You-Qiang
YQ
Chan
Danny
D
Cheung
Kenneth M C
KM
Wong
Kenneth Kak-Yuen
KK
Cherny
Stacey S
SS
Sham
Pak-Chung
PC
Tam
Paul Kwong-Hang
PK
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
D005819:Genetic Markers; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D051096:Proto-Oncogene Proteins c-ret