Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
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DOI：
10.1073/pnas.0809630105
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Tam, Paul Kwong-hang
中科院分区：
文献类型：
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作者：
Garcia-Barcelo, Maria-Merce;Tang, Clara Sze-man;Tam, Paul Kwong-hang
先天性巨结肠 (HSCR) 或无神经节巨结肠是一种先天性疾病，其特征是远端肠道的不同部分缺乏肠神经节。 RET 是一个公认的易感基因座，尽管现有证据强烈表明其他基因座有助于散发性 HSCR。为了识别这些额外的基因位点，我们使用 Affymetrix 500K 标记集进行了全基因组关联研究。我们成功对 181 名散发性 HSCR 的中国受试者和 346 名种族匹配的对照受试者的 293,836 个 SNP 进行了基因分型。与 HSCR 最相关的 SNP 在一组独立的 190 名 HSCR 受试者和 510 名对照受试者中进行了基因分型。除了 RET 中的 SNP 之外，在 8p12 上位于神经调节蛋白 1 基因 (NRG1) 内含子 1 的 2 个 SNP 中发现了似是而非的候选基因中最强的整体关联，其中 rs16879552 和 rs7835688 的比值比为 1.68 [CI95%:(1.40, 2.00), P = 1.80 x对于加法模型下的杂合风险基因型，分别为 10(-8)] 和 1.98 [CI95%:(1.59, 2.47), P = 1.12x10(-9)]。 RET 和 NRG1 之间也存在显着的相互作用 (P = 0.0095)，在 NRG1 rs7835688 杂合子存在的情况下，RET rs2435357 风险基因型 (TT) 的比值比增加 2.3 倍，达到 19.53，表明 NRG1 是 HSRC 外显率的调节剂。我们高度显着的关联发现得到了 NRG1 作为肠神经节前体发育调节因子的重要作用的支持。 NRG1 被鉴定为额外的 HSCR 易感基因座，不仅开启了对 HSCR 病理学机制的独特研究领域，而且还开启了离散数量的基因座相互作用导致疾病的机制。
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 [CI95%:(1.40, 2.00), P = 1.80 x 10(-8)] and 1.98 [CI95%:(1.59, 2.47), P = 1.12x10(-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.