Zhong Yuanxin, So Man-Ting, Ma Zuyi, Zhang Detao, Wang Yanbing, Xiong Zewei, Fadista João, Song You-Qiang, Cheah Kathryn Song-Eng, Alves Maria M, Borrego Salud, Ceccherini Isabella, Pakarinen Mikko P, Feenstra Bjarke, Lui Vincent Chi-Hang, Garcia-Barcelo Maria-Merce, Sham Pak Chung, Tam Paul Kwong-Hang, Tang Clara Sze-Man
Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China.
Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China.
EBioMedicine. 2025 May;115:105680. doi: 10.1016/j.ebiom.2025.105680. Epub 2025 Apr 3.
Hirschsprung disease (HSCR) is a rare, congenital disease characterized by the absence of enteric ganglia in the hindgut. Common genetic variation contributes substantially to the heritability of the disease yet only three HSCR-associated loci were identified from genome-wide association studies (GWAS) thus far.
We performed the largest multi-ancestry meta-analysis of GWAS to date, totalling 1250 HSCR cases and 7140 controls. Prioritized candidate genes were further characterized using single-cell transcriptomic data of developing human and mouse gut for their roles in development of enteric nervous system (ENS). Functional characterisation using human cells and zebrafish models was performed. Global and ancestry-matched polygenic risk score (PRS) models were derived and evaluated for predicting risk of HSCR.
We identified four HSCR-susceptibility loci, with three loci (JAG1, HAND2 and ZNF25) reaching genome-wide significance and one putative locus (UNC5C) prioritized by functional relevance. Spatiotemporal analysis revealed hotspots of gene dysregulation during ENS development. Functional analyses further demonstrated that knockdown of the candidate genes impaired cell migration and zebrafish knockouts displayed abnormal ENS development. We also demonstrated comparable performance for a PRS model derived from multi-ancestry meta-analysis to those of ancestry-matched PRS models, supporting its potential clinical application in risk prediction of HSCR across populations.
Overall, the meta-analysis implicated novel genes, pathways and spatiotemporal developmental hotspots in the genetic aetiology of HSCR. Development of a PRS universally applicable irrespective of ancestries may leverage its clinical utility in risk prediction.
The full list of funding bodies can be found in the Acknowledgements section.
先天性巨结肠病（HSCR）是一种罕见的先天性疾病，其特征是后肠中缺乏肠神经节。常见的基因变异对该疾病的遗传度有很大贡献，但迄今为止，全基因组关联研究（GWAS）仅鉴定出3个与HSCR相关的基因座。
我们进行了迄今为止最大规模的多血统GWAS荟萃分析，共有1250例HSCR病例和7140例对照。使用发育中的人类和小鼠肠道的单细胞转录组数据进一步表征优先候选基因，以确定它们在肠神经系统（ENS）发育中的作用。利用人类细胞和斑马鱼模型进行功能表征。推导并评估了全球和血统匹配的多基因风险评分（PRS）模型，以预测HSCR风险。
我们鉴定出4个HSCR易感基因座，其中3个基因座（JAG1、HAND2和ZNF25）达到全基因组显著性水平，1个推定基因座（UNC5C）因功能相关性而被优先考虑。时空分析揭示了ENS发育过程中基因失调的热点。功能分析进一步表明，候选基因的敲低会损害细胞迁移，斑马鱼基因敲除显示ENS发育异常。我们还证明，多血统荟萃分析得出的PRS模型与血统匹配的PRS模型具有相当的性能，支持其在跨人群HSCR风险预测中的潜在临床应用。
总体而言，荟萃分析揭示了HSCR遗传病因中的新基因、途径和时空发育热点。开发一种不考虑血统普遍适用的PRS可能会提高其在风险预测中的临床效用。
资金机构的完整列表可在致谢部分找到。
