Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

Guo Cheng, Clara Sze Man Tang, Emily Hoi Man Wong, William Wai Chun Cheng, Man Ting So, Xiaoping Miao, Ruizhong Zhang, Long Cui, Xuelai Liu, Elly Sau Wai Ngan, Vincent Chi Hang Lui, Patrick Ho Yu Chung, Ivy Hau Yee Chan, Juncheng Liu, Wei Zhong, Huimin Xia, Jiakang Yu, Xiu Qiu, Xuan Zhao Wu, Bin Wang & 13 others Xiao Dong, Jinfa Tou, Liuming Huang, Bin Yi, Hongxia Ren, Edwin Kin Wai Chan, Qian K. Ye, Paul F. O'Reilly, Kenneth Kak Yuen Wong, Pak Chung Sham, Stacey S. Cherny, Paul Kwong Hang Tam, Maria Mercè Garcia-Barceló

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1285-1291
Number of pages7
JournalJournal of Hepatology
Volume59
Issue number6
DOIs
StatePublished - Dec 2013

Fingerprint

Biliary Atresia
Gene Expression
Single Nucleotide Polymorphism
Haplotypes
Genome-Wide Association Study
Population
Alleles
Computational Biology
Epidemiology
Odds Ratio
Genotype
Newborn Infant
Confidence Intervals
Mutation
Liver
Incidence
Genes

Keywords

  • Epidemiology
  • Expression quantitative trait loci
  • Natural selection
  • Rare complex disease

ASJC Scopus subject areas

  • Hepatology

Cite this

Cheng, G., Tang, C. S. M., Wong, E. H. M., Cheng, W. W. C., So, M. T., Miao, X., ... Garcia-Barceló, M. M. (2013). Common genetic variants regulating ADD3 gene expression alter biliary atresia risk. Journal of Hepatology, 59(6), 1285-1291. https://doi.org/10.1016/j.jhep.2013.07.021

Common genetic variants regulating ADD3 gene expression alter biliary atresia risk. / Cheng, Guo; Tang, Clara Sze Man; Wong, Emily Hoi Man; Cheng, William Wai Chun; So, Man Ting; Miao, Xiaoping; Zhang, Ruizhong; Cui, Long; Liu, Xuelai; Ngan, Elly Sau Wai; Lui, Vincent Chi Hang; Chung, Patrick Ho Yu; Chan, Ivy Hau Yee; Liu, Juncheng; Zhong, Wei; Xia, Huimin; Yu, Jiakang; Qiu, Xiu; Wu, Xuan Zhao; Wang, Bin; Dong, Xiao; Tou, Jinfa; Huang, Liuming; Yi, Bin; Ren, Hongxia; Chan, Edwin Kin Wai; Ye, Qian K.; O'Reilly, Paul F.; Wong, Kenneth Kak Yuen; Sham, Pak Chung; Cherny, Stacey S.; Tam, Paul Kwong Hang; Garcia-Barceló, Maria Mercè.

In: Journal of Hepatology, Vol. 59, No. 6, 12.2013, p. 1285-1291.

Research output: Contribution to journalArticle

Cheng, G, Tang, CSM, Wong, EHM, Cheng, WWC, So, MT, Miao, X, Zhang, R, Cui, L, Liu, X, Ngan, ESW, Lui, VCH, Chung, PHY, Chan, IHY, Liu, J, Zhong, W, Xia, H, Yu, J, Qiu, X, Wu, XZ, Wang, B, Dong, X, Tou, J, Huang, L, Yi, B, Ren, H, Chan, EKW, Ye, QK, O'Reilly, PF, Wong, KKY, Sham, PC, Cherny, SS, Tam, PKH & Garcia-Barceló, MM 2013, 'Common genetic variants regulating ADD3 gene expression alter biliary atresia risk', Journal of Hepatology, vol. 59, no. 6, pp. 1285-1291. https://doi.org/10.1016/j.jhep.2013.07.021
Cheng, Guo ; Tang, Clara Sze Man ; Wong, Emily Hoi Man ; Cheng, William Wai Chun ; So, Man Ting ; Miao, Xiaoping ; Zhang, Ruizhong ; Cui, Long ; Liu, Xuelai ; Ngan, Elly Sau Wai ; Lui, Vincent Chi Hang ; Chung, Patrick Ho Yu ; Chan, Ivy Hau Yee ; Liu, Juncheng ; Zhong, Wei ; Xia, Huimin ; Yu, Jiakang ; Qiu, Xiu ; Wu, Xuan Zhao ; Wang, Bin ; Dong, Xiao ; Tou, Jinfa ; Huang, Liuming ; Yi, Bin ; Ren, Hongxia ; Chan, Edwin Kin Wai ; Ye, Qian K. ; O'Reilly, Paul F. ; Wong, Kenneth Kak Yuen ; Sham, Pak Chung ; Cherny, Stacey S. ; Tam, Paul Kwong Hang ; Garcia-Barceló, Maria Mercè. / Common genetic variants regulating ADD3 gene expression alter biliary atresia risk. In: Journal of Hepatology. 2013 ; Vol. 59, No. 6. pp. 1285-1291.
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abstract = "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.",
keywords = "Epidemiology, Expression quantitative trait loci, Natural selection, Rare complex disease",
author = "Guo Cheng and Tang, {Clara Sze Man} and Wong, {Emily Hoi Man} and Cheng, {William Wai Chun} and So, {Man Ting} and Xiaoping Miao and Ruizhong Zhang and Long Cui and Xuelai Liu and Ngan, {Elly Sau Wai} and Lui, {Vincent Chi Hang} and Chung, {Patrick Ho Yu} and Chan, {Ivy Hau Yee} and Juncheng Liu and Wei Zhong and Huimin Xia and Jiakang Yu and Xiu Qiu and Wu, {Xuan Zhao} and Bin Wang and Xiao Dong and Jinfa Tou and Liuming Huang and Bin Yi and Hongxia Ren and Chan, {Edwin Kin Wai} and Ye, {Qian K.} and O'Reilly, {Paul F.} and Wong, {Kenneth Kak Yuen} and Sham, {Pak Chung} and Cherny, {Stacey S.} and Tam, {Paul Kwong Hang} and Garcia-Barcel{\'o}, {Maria Merc{\`e}}",
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TY - JOUR

T1 - Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

AU - Cheng, Guo

AU - Tang, Clara Sze Man

AU - Wong, Emily Hoi Man

AU - Cheng, William Wai Chun

AU - So, Man Ting

AU - Miao, Xiaoping

AU - Zhang, Ruizhong

AU - Cui, Long

AU - Liu, Xuelai

AU - Ngan, Elly Sau Wai

AU - Lui, Vincent Chi Hang

AU - Chung, Patrick Ho Yu

AU - Chan, Ivy Hau Yee

AU - Liu, Juncheng

AU - Zhong, Wei

AU - Xia, Huimin

AU - Yu, Jiakang

AU - Qiu, Xiu

AU - Wu, Xuan Zhao

AU - Wang, Bin

AU - Dong, Xiao

AU - Tou, Jinfa

AU - Huang, Liuming

AU - Yi, Bin

AU - Ren, Hongxia

AU - Chan, Edwin Kin Wai

AU - Ye, Qian K.

AU - O'Reilly, Paul F.

AU - Wong, Kenneth Kak Yuen

AU - Sham, Pak Chung

AU - Cherny, Stacey S.

AU - Tam, Paul Kwong Hang

AU - Garcia-Barceló, Maria Mercè

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

KW - Epidemiology

KW - Expression quantitative trait loci

KW - Natural selection

KW - Rare complex disease

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