Research Paper Volume 12, Issue 8 pp 7163—7182

Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility

Mei-Rong Bai 1, 2, 3, *, , Wei-Bo Niu 1, 2, 3, *, , Ying Zhou 1, 2, 3, *, , Yi-Ming Gong 1, 2, 3, , Yan-Jiao Lu 2, 3, , Xian-Xian Yu 2, 3, , Zhi-Liang Wei 2, 3, , Wenjie Wu 1, 2, 3, , Huan-Lei Song 2, 3, , Wen-Wen Yu 2, 3, , Bei-Lin Gu 2, 3, , Wei Cai 1, 2, 3, , Xun Chu 1, 2, 3, ,

  • 1 Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 2 Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
  • 3 Shanghai Institute of Pediatric Research, Shanghai, China
* Equal contribution

received: November 13, 2019 ; accepted: March 29, 2020 ; published: April 21, 2020 ;
How to Cite

Copyright © 2020 Bai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.


BA: biliary atresia; GWAS: genome-wide association study; SNP: single nucleotide polymorphism; eQTL: expression quantitative trait loci; LD: linkage disequilibrium; ADD3: adducin 3; GPC1: glypican 1; ARF6: adenosine diphosphate-ribosylation factor-6; EFEMP1: epidermal growth factor-containing fibulin-like extracellular matrix protein 1; XPNPEP1: X prolyl aminopeptidase P1 soluble; HWE: Hardy-Weinsberg equilibrium; MAFs: minor allele frequencies; OR: odds ratio; CI: confidence interval; GMDR: Generalized multifactor dimensionality reduction; ROC: receiver operating characteristic; AUC: area under the curve; GTEx: Genotype-Tissue Expression; PPI: protein-protein interaction; SHH: Sonic Hedgehog; CDH1: cadherin 1; GLI1: glioma-associated oncogene homolog 1; SMO: smoothened; MO: morpholino antisense oligonucleotide; EMT: epithelial-mesenchymal transitions; GPC3: glypican-3; PCR: polymerase chain reaction.