title: Genome-wide association studies in biliary atresia.
abstract: Biliary atresia (BA) is a model complex disease resulting from interactions between multiple susceptibility loci and environmental factors. This perception is based on a heterogeneous phenotype extending beyond an absent extrahepatic bile duct to include gut and cardiovascular anomalies, and the association of BA with viral infections. Refractory jaundice and progression to cirrhosis shortly after birth can be fatal without surgical correction, and further suggests a pathogenesis during liver and bile duct development. Conclusive proof for a developmental origin would require documentation of disease progression in the perinatal or fetal liver, an impossible task for obvious reasons. We review three different sets of genome-wide association studies (GWAS) from three different cohorts of BA patients by three different groups of investigators, which address this knowledge gap. Knockdown of each susceptibility gene identified by GWAS in zebrafish embryos impairs excretion of bile from the liver, duplicating the characteristic diagnostic finding seen in affected children. This finding is associated with impaired intrahepatic biliary network formation in zebrafish morphants. Although distinct, these susceptibility genes share several functions including roles in mechanisms for organogenesis (glypican 1 or GPC1, and adenosine diphosphate ribosylation factor 6, or ARF6) or a greater expression in fetal liver than in adult liver (adducin 3 or ADD3). Together, these studies emphasize the importance of the human evidence, and present opportunities to map novel pathways which explain the phenotypic heterogeneity of BA.
authors.affiliation: Department of Surgery, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
authors.forename: Mylarappa
authors.initials: M
authors.lastname: Ningappa
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Surgery, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.affiliation: Department of Surgery, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.affiliation: Department of Surgery, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: Department of Surgery, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D000328:Adult; D000818:Animals; D001656:Biliary Atresia / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000196:embryology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D038081:Organogenesis / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins