Rare and common genetic variants underlying the risk of Hirschsprung’s disease

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.

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Publication Details

Journal
Human Molecular Genetics
Published
2025-01-16
DOI
https://doi.org/10.1093/hmg/ddae205
Citations
4
Primary Topic
Congenital gastrointestinal and neural anomalies
Type
article
Field-Weighted Citation Impact
8.03

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article

Rare and common genetic variants underlying the risk of Hirschsprung’s disease

Jun Xiao, Xingjie Hao, Jiexiong Feng, Feng Chen et al.
4 citations
Human Molecular Genetics
Congenital gastrointestinal and neural anomalies
8.03
article

Rare and common genetic variants underlying the risk of Hirschsprung’s disease

Jun Xiao, Xingjie Hao, Jiexiong Feng, Feng Chen, Didi Zhuansun, Tianqi Zhu, Jingyi You, Yuanmei Liu, Lei Yu, Yi Wang, Bingyan Zhou, Chenzhao Feng, Xinyao Meng, Dianming Wu, Xiaosi Yu, Xuyong Chen, Zhilin Xu, Heying Yang, Mei Yu, Qi Chen, Xuan Zhang, Jing Wang, Qiong Wang, Hongxia Ren, Qiang Yin, Zejian Li, Bo Xiong, Xiaojuan Wu, Xuewu Jiang, Jie Tang, Donghai Yu, Lei Xiang, Jinfa Tou, Jixin Yang, Xiang Liu
article en
4 citations

Abstract

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.

Human Molecular GeneticsVol. 34(7)
Fujian Medical University (CN), Harbin Medical University (CN), Zunyi Medical University (CN), Shantou University (CN), Nanjing Children's Hospital (CN), Shenzhen Maternity and Child Healthcare Hospital (CN), Children's Hospital of Zhejiang University (CN), Guiyang University (CN), Second Affiliated Hospital of Shantou University Medical College (CN), Fuzhou Maternity and Child Health Care Hospital (CN), Hunan Children's Hospital (CN), Second Affiliated Hospital of Nanjing Medical University (CN), Wuhan Children's Hospital (CN), Third Affiliated Hospital of Zhengzhou University (CN), Anhui Provincial Children's Hospital (CN), Shanxi Provincial Children's Hospital (CN), First Affiliated Hospital of Harbin Medical University (CN), First Affiliated Hospital of Zhengzhou University (CN), Children's Hospital of Chongqing Medical University (CN), Tongji Hospital (CN), Union Hospital (CN), Affiliated Hospital of Zunyi Medical College (CN), Huazhong University of Science and Technology (CN), Hubei University (CN), Chongqing Medical University (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation
Good health and well-being
Openalex Percentile: Top 3%
Congenital gastrointestinal and neural anomalies
8.03
DOISourceOpenAlex
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