Biliary atresia (BA) is a rare and severe cholestatic disease in neonates characterized by an idiopathic inflammatory process affecting both intra- and extra-hepatic bile ducts, causing cholestasis and ultimately leading to obliteration of the biliary tract. Through a previous genome-wide-association-study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 gene. But disease pathogenesis and genetic architecture of BA is still obscure. We mapped the 10q24.2 association locus with 107 single nucleotide polymorphisms (SNPs) on 339 Han Chinese patients and 401 matched controls, follow-up studies of the association signals were performed. We revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [logistic regression p=5.32x10-11; odds ratio, OR:2.38; confidence interval, CI:(2.14-2.62)]. No deleterious rare variants (RVs) residing on the risk haplotype were found, dismissing the theory of “synthetic” association. Moreover, the BA-associated potential regulatory SNPs correlated ADD3 gene expression (linear regression p=0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the general population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus. Our finding suggested the complexity of BA genetic architecture and role of environmental effects in the disease. We then revisited BA GWAS dataset and annotated the association signals with expression quantitative trail loci (eQTL) information available on normal adult livers. We did not see excessive enrichment of BA associated SNPs in liver eQTLs. We speculate that the liver eQTLs currently available relate to adulthood liver function and are not necessarily involved in liver development, adaptation to oxidative stress, or inflammation changes seen in BA pathophysiology. To investigate whether rare alleles can predispose to BA, we called copy number variations (CNVs) from the GWAS Affymetrix gene chip 5.0. We obtained 86 BA private CNVs distributed among 131 BA patients were compared to the CNV profile of 11,943 database samples and 846 hypertension disease samples. Assuming that pathogenic CNVs interrupt dosage-sensitive genes, we prioritized the dosage-sensitive genes and the pathogenic CNVs by integrating multiple lines of evidence. Through gene set enrichment analysis we found that the ‘core’ genes affected by BA CNVs were members of the Calcium signaling pathway, which has been involved in the pathogenesis of polycystic liver and kidney diseases. Further we initiated the survey on rare coding variants in BA through Exome sequencing 23 BA liver genomes, while patients’ blood DNA and parental DNA would be examined in the validation stage to validate de novo mutations, including somatic mosaicism in liver. We found inherited deleterious mutations in polycystic liver and kidney disease genes in BA patients, and the role of these mutations in BA pathogenesis is being investigated. Functional validation of the BA variants identified in this study is compulsory given the overall obscurity of BA pathogenesis. Together, this study presents a comprehensive catalog of both common and rare variants implicated in BA. We hope that our findings will contribute to enriching the BA-associated genetic network. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Psychiatry / Master / Master of Philosophy