胆道闭锁（BA）为全面理解且需要肝移植（LT）的疾病，儿童终身需要免疫抑制治疗。为了确定其遗传基础，我们在美国、加拿大和英国的医疗中心对811个欧洲BA病例进行了GWAS，并与4654个基因匹配的对照组进行了比较。通过对100例病例进行全基因组测序，评估罕见变异的合成关联。功能研究包括对64例BA病例的整个肝脏转录组分析和实验模型的扰乱。GWAS分析常见的单核苷酸多态性位点（≥1%的等位基因频率），确定了具有全基因组显著性（p=3.93E-8）的AFAP1内含子位点rs6446628和亚阈全基因组显著性（p=1.34E-7）的TUSC3位点rs34599046，均有相邻单核苷酸多态性位点的可靠峰值支持。与以前报道的与BA相关基因一样，AFAP1和TUSC3是纤毛生成和平面极性因子（CPLANE）。基于基因集的GWAS表明，BA与102个CPLANE基因中的6005个SNP相关（p=5.84E-15）。与非CPLANE基因相比，更多的CPLANE基因携带了罕见变异（等位基因频率<1%），这些变异通过预测算法与与肝胆异常相关的人类表型本体术语相吻合，分别为75%和40%，p<0.0001。在大多数BA病例中，罕见变异存在于与与BA相关的常见变异不同的多个基因中。AFAP1和TUSC3沉默可阻断小鼠气管细胞的纤毛生成。纤毛生成的抑制导致斑马鱼胆道畸形。AFAP1和TUSC3在胎儿肝器官、胎儿和BA肝中表达，而在正常或疾病对照的肝中不表达。BA相关变异和肝转录物的综合分析显示异常的血管生成和上皮管形成，解释了BA伴随的门静脉异常。胆道闭锁与CPLANE基因中的多基因易感性相关。罕见变异通过不同于BA相关常见变异的独特基因在易感途径中起到了多基因风险的贡献。肝移植是治愈胆道闭锁的需求，但不了解该疾病机制。移植免疫抑制增加了生命威胁性感染和癌症的发生几率。为了改善通过预防该疾病及其发展为移植而提供的护理，我们研究了其遗传基础。我们发现该疾病与独特基因中的常见和罕见突变相关，这些基因在早期胚胎发育过程中维持细胞正常通讯和运动以及它们组织成胆道和血管。由于这些基因的缺陷也会导致其他先天缺陷，我们的发现可以引导预防策略，降低胆道闭锁和潜在其他先天缺陷的发生率。版权所有 © 2023. Elsevier B.V. 发表。

Biliary atresia (BA) is poorly understood and requires liver transplantation (LT) in most children with lifelong risks of immunosuppression.To determine its genetic basis, we performed GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4654 genetically matched controls. Whole genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.GWAS of common SNPs, allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p=3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p=1.34E-7), both supported with credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA associated with 6005 SNPs in 102 CPLANE genes (p=5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants, (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 75% vs 40%, p<0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants, in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, fetal and BA liver but not normal or disease-control liver. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA.Biliary atresia is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes.Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialised genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings can lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.Copyright © 2023. Published by Elsevier B.V.