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Mapping Disease Pathways for Biliary Atresia

Biliary atresia (BA) is a poorly understood rare disease that causes jaundice and liver failure at birth due to underdeveloped bile ducts. Associated defects include poor development of the portal vein and involvement of non-hepatic organs. After initial surgical drainage in all patients, the majority need liver transplantation because of progressive cirrhosis. In addition to the risks of lifelong immunosuppression after liver transplantation, the post-transplant biliary atresia patient can experience surgical complications like portal vein thrombosis along with the consequences of extrahepatic involvement often found in affected patients.

To determine the genetic basis of this disease, a genome-wide association study of 811 BA cases, all of whom received liver transplantation, and 4654 controls was performed with a 2.5 million SNP array. The study found that BA associates with polygenic risk conferred by over 6000 common variants, minor allele frequencies >1%, in 102 ciliogenesis and planar polarity effector genes (CPLANE). Whole genome sequencing of 100 of 811 cases revealed that most cases harbored rare variants, allele frequencies <1%, which were also more likely to be present in CPLANE genes. Whole transcriptome sequencing of diseased liver from 64 of 811 subjects and its integrative analysis with disease associated SNPs revealed dysregulated vascular and epithelial tube development. In perturbation studies, the top-ranked BA-associated loci showed expression of the corresponding proteins in fetal and biliary atresia liver, but not in normal liver or liver from disease controls.

Whole genome genotyping, gene expression and whole genome sequencing data is being made available.