Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2

Abstract

Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA proposes that during the perinatal period, a still unknown exogenous factor meets the innate immune system of a genetically predisposed individual and induces an uncontrollable and potentially self-limiting immune response, which becomes manifest in liver fibrosis and atresia of the extrahepatic bile ducts. Genetic factors that could account for the disease, let alone for its high incidence in Chinese, are to be investigated. To identify BA susceptibility loci, we carried out a genome-wide association study (GWAS) using the Affymetrix 5.0 and 500 K marker sets. We genotyped nearly 500 000 single-nucleotide polymorphisms (SNPs) in 200 Chinese BA patients and 481 ethnically matched control subjects. The 10 most BA-associated SNPs from the GWAS were genotyped in an independent set of 124 BA and 90 control subjects. The strongest overall association was found for rs17095355 on 10q24, downstream XPNPEP1, a gene involved in the metabolism of inflammatory mediators. Allelic chi-square test P-value for the meta-analysis of the GWAS and replication results was 6.94 x 10(-9). The identification of putative BA susceptibility loci not only opens new fields of investigation into the mechanisms underlying BA but may also provide new clues for the development of preventive and curative strategies.

Figure 1.

Results of the GWAS. (A) The Cochran–Armitage significance test results after EIGENSTRAT correction for population stratification. (B) Q–Q plot revealing deviation of association from expected, starting from P = 5 × 10⁻⁴ (green before and red after EIGENSTRAT correction) (standard error in blue).

Figure 2.

Genomic context for the BA-associated peak on 10q24.2. −log(P) value for the BA-associated SNPs rs17095355 (blue diamond) and rs2501577. Also shown is the position of recombination hotspots (light blue line at the bottom of top panel). Genes in the region are represented by green lines with arrow heads indicating the sense of transcription. The color of the nearby SNPs (diamond) depends on its r² with the associated SNP: red, ≥0.8; orange, ≥0.5 and <0.8; yellow, ≥0.2 and <0.5; white, <0.2. Chromosome position is plotted with reference to the NCBI build 35 and gene names are plotted with reference to the University of California at Santa Cruz Genome Browser. Recombination rate estimated from the HapMap is plotted in light blue. In the bottom panel, LD structures based on pair-wise r² in the associated region in the CHB and JPT population are shown. The SNPs with the strongest association are highlighted in white and nearby SNPs also on the GWAS SNP panel in green. Other SNPs are in black.