Integrating genetic analysis with phenotypes of biliary atresia

Abstract

We aim to explore the role of rare copy number variants (CNVs) in non-syndromic BA. We revisited clinical records of 89 non-syndromic type III BA patients with median follow up of 17.20 years, which revealed that 41.57% BAs were affected with chronic extra-hepatic diseases, with high prevalence of autoimmune-allergic diseases (22.47%) and Glucose-6-phosphate dehydrogenase deficiency (14.29% of the males). After genotyping on the genome- wide Affymetrix5.0 array, we shortlisted 29 ‘BA-CNVs’ found in BA patients but not in the general population, and collated 103 BA-associated genes from a gene-based genome-wide association analysis on common variants, for downstream analysis. In BA-CNVs we discovered three categories of genotype- phenotype correlations: i) two de novo BA-CNVs, perturbing genes/ chromosome-segments known to BA, correlated with BA; ii) three BA-CNVs encompassing genes known to immunity defects, correlated with comorbiditiescomorbidities of those immune disorders in 3 carriers; iii) importantly, genes affected by BA-CNVs (N=102; gene set-1) were enriched with immune genes, correlated with the high prevalence of immunity disorders in BA. Further, we proved significant connectivity between gene set-1 and genes tagged by common variants (N=103; gene set-2) (Empirical p=0.039). As multiple function modules were elucidated in topological analysis of the BA candidate gene network, a ‘core’ position of cellular signalling pathways, which affect inflammatory and immunity regulation pathways, was highlighted. Conclusions: BA-CNVs underpin BA phenotypic complexity, and converge with those BA-associated common variants in a molecular network implicated in BA pathogenesis. Integrating clinical/epidemiological data and BA genetic findings is plausible using the BA ‚diseasome‘ approach.