Background & Aims Biliary atresia (BA) is a rare and most severe cholestatic disease in neonates, but the pathogenic mechanisms are unknown. Through a previous genome wide association study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was replicated in Chinese and Thai populations. This study aims to fully characterize the genetic architecture at 10q24.2 and to reveal the link between the genetic variants and BA. Methods We genotyped 107 single nucleotide polymorphisms (SNPs) in 10q24.2 in 339 Han Chinese patients and 401 matched controls using Sequenom. Exhaustive follow-up studies of the association signals were performed. Results The combined BA-association p-value of the GWAS SNP (rs17095355) achieved 6.06 × 10-10. Further, we revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [p = 5.32 × 10-11; odds ratio, OR: 2.38; confidence interval, CI: (2.14-2.62)]. Through Sanger sequencing, no deleterious rare variants (RVs) residing in the risk haplotype were found, dismissing the theory of "synthetic" association. Moreover, in bioinformatics and in vivo genotype-expression investigations, the BA-associated potentially regulatory SNPs correlated with ADD3 gene expression (n = 36; p = 0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus, suggesting a possible role for the BA-associated common variants in shaping the general population diversity. Conclusions Common genetic variants in 10q24.2 can alter BA risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population.
- Expression quantitative trait loci
- Natural selection
- Rare complex disease