Genome-wide association analysis implicates dysregulation of Wnt signaling pathway in biliary atresia

Abstract

Biliary Atresia (BA) is a severe, complex hepatobiliary disorder and is a major cause of neonatal cholestasis. It is characterized by progressive fibrosclerosing and inflammatory obliteration of the biliary system in response to unknown insult during the first few weeks of life. Recent genetic researches revealed several BA-susceptibility loci with common risk alleles predisposing to BA; however, the genetic basis of BA and its underlying disease mechanisms remain largely unexplored. With the aim of identifying novel BA-associated variants, we conducted a meta-analysis of genomewide association studies (GWAS), including 489 non-syndromic BA cases and 1044 controls of East Asian ancestry. We uncovered two BA-associated loci with low frequency variants marginally associated with BA (USP34: P=2.9x10-7; OR=3.02 [95% confidence interval(CI): 1.98-4.60] and PTPRZ1: P=7.8x10-7; OR=2.12 [95% CI: 1.57-2.86]). Both USP34 and PTPRZ1 play important roles in Wnt/β-catenin signalling and were reported to be dysregulated upon liver injury. Specially, BA patients with liver transplant have three times higher risk allele frequency for the top variant at USP34 (~11.7%) than controls and the frequency is also higher than those BA patients without transplant. Our results showed that Wnt/β-catenin signalling may underlie both the aetiology and progression of BA.