title: Common genetic variants regulating ADD3 gene expression alter biliary atresia risk.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.forename: Emily Hoi-Man
authors.initials: EH
authors.lastname: Wong
authors.forename: William Wai-Chun
authors.initials: WW
authors.lastname: Cheng
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Zhang
authors.forename: Long
authors.initials: L
authors.lastname: Cui
authors.forename: Xuelai
authors.initials: X
authors.lastname: Liu
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Patrick Ho-Yu
authors.initials: PH
authors.lastname: Chung
authors.forename: Ivy Hau-Yee
authors.initials: IH
authors.lastname: Chan
authors.forename: Juncheng
authors.initials: J
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Huimin
authors.initials: H
authors.lastname: Xia
authors.forename: Jiakang
authors.initials: J
authors.lastname: Yu
authors.forename: Xiu
authors.initials: X
authors.lastname: Qiu
authors.forename: Xuan-Zhao
authors.initials: XZ
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Dong
authors.forename: Jinfa
authors.initials: J
authors.lastname: Tou
authors.forename: Liuming
authors.initials: L
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Yi
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ren
authors.forename: Edwin Kin-Wai
authors.initials: EK
authors.lastname: Chan
authors.forename: Kenny
authors.initials: K
authors.lastname: Ye
authors.forename: Paul F
authors.initials: PF
authors.lastname: O'Reilly
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
mesh_terms: D001656:Biliary Atresia / Q000209:etiology / Q000235:genetics*; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; C102021:ADD3 protein, human; D000099291:Adducins
keywords: AIC; Akaike Information Criterion; BA; CEU; CHB; CI; Chinese Han from Beijing; EM; EMP; Epidemiology; Expression quantitative trait loci; F; Fst; GLM; GWAS; IHC; JPT; Japanese from Tokyo; LD; MAF; NCBI; National Center for Biotechnology Information; Natural selection; OR; PCR; QC; RV; Rare complex disease; SNP; TF; Utah residents with ancestry from northern and western Europe; YRI; Yoruba in Ibadan; biliary atresia; confidence interval; empirical p value; expectation-maximization; fixation index; fraction of significantly differentiated SNPs; generalized linear-regression model; genome-wide association study; immunohistochemistry; linkage disequilibrium; minor allele frequency; odds ratio; polymerase chain reaction; quality control; rare variants; single nucleotide polymorphism; transcription factor