Genome-wide association study identifies susceptibility loci for biliary atresia

Abstract

Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first weeks of life. The incidence of BA ranges from 1 in 5000 to 1 in 18,000 in different populations, the highest being found in Chinese. Despite early diagnosis and prompt surgical intervention, the disease progresses to cirrhosis in many patients. Reported cases of familial BA, together with immunochemistry and gene expression studies on liver tissues, suggest that the immunogenetic vulnerability of the patients to the precipitating factors is likely to play a role in the susceptibility to develop BA. To find susceptibility loci for BA, we conducted genome-wide SNP association study using Affymetrix SNP arrays assaying approximately 500,000 markers on 150 patients and 351 controls. Genotype calling was done using the Birdseed V2 algorithm, yielding an average call rate of 96%. As a preliminary control for stratification, samples were clustered using Multidimensional Scaling (MDS) and the nearest neighbor analysis implemented in PLINK. Samples with evidence of admixture were consequently excluded. To further ensure the accuracy of the study, samples were subjected to biological relationship and cross-examination verification by using the GRR program. SNPs with minor allele frequency less than 5% and call rate lower than 93% were filtered out to produce a panel of around 290K high quality SNPs for genome wide association tests. After stringent quality control, the association tests were conducted on 142 BA patients and 322 controls. Initial data revealed suggestive susceptibility loci on 10q24.2, 5q31.5, and 12q13.3 chromosomal regions.