Xiao Jun, Feng Chenzhao, Zhu Tianqi, Zhang Xuan, Chen Xuyong, Li Zejian, You Jingyi, Wang Qiong, Zhuansun Didi, Meng Xinyao, Wang Jing, Xiang Lei, Yu Xiaosi, Zhou Bingyan, Tang Weibing, Tou Jinfa, Wang Yi, Yang Heying, Yu Lei, Liu Yuanmei, Jiang Xuewu, Ren Hongxia, Yu Mei, Chen Qi, Yin Qiang, Liu Xiang, Xu Zhilin, Wu Dianming, Yu Donghai, Wu Xiaojuan, Yang Jixin, Xiong Bo, Chen Feng, Hao Xingjie, Feng Jiexiong
Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China.
Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China.
Hum Mol Genet. 2025 Mar 20;34(7):586-598. doi: 10.1093/hmg/ddae205.
Hirschsprung's disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.
先天性巨结肠症（HSCR）是一种先天性肠道神经病变性疾病，具有高遗传性（>80%）和多基因遗传特征（>20个基因）。以往的全基因组关联研究（GWAS）确定了几个与HSCR相关的常见变异，并证明使用遗传风险评分在欧洲人群中对HSCR风险的预测性能有所提高，但关于中国人群的知识仍存在显著差距。我们对中国的一个HSCR病例队列进行了全外显子组测序。通过使用共同对照（来自1000基因组计划东亚人群的505名对照和来自中国代谢组数据库的10588名对照），我们对全外显子组中的常见变异进行了GWAS，并对罕见变异进行了基于基因的关联分析。我们在重复样本以及体外和体内实验中进一步验证了相关的变异和基因。我们通过GWAS鉴定出一个新基因PLK5，并基于基因检测提出了45个新的假定基因。通过使用RET和PLK5的遗传变异，我们构建了一个遗传风险评分，该评分可以识别出具有非常高的HSCR遗传风险的个体。与来自这三个变异的零个或一个风险等位基因的患者相比，具有六个等位基因的患者患HSCR的风险高出36.61倍。此外，我们描绘了一个包含57个基因的HSCR风险基因图谱，该图谱分别解释了中国人群和欧洲人群中88.5%和54.5%的HSCR。总之，本研究提高了对HSCR遗传结构的认识，并为中国人群的HSCR提供了一种风险预测方法。
