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Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia

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Abstract

In the United States, biliary atresia (BA) is the most frequent indication for liver transplantation in pediatric patients. BA is a complex disease, with suspected environmental and genetic risk factors. A genome-wide association study in Chinese patients identified association to the 10q24.2 (hg18) genomic region. This signal was upstream of two genes, XPNPEP1 and ADD3, both expressed in intrahepatic bile ducts. We tested association to this region in 171 BA patients and 1,630 controls of European descent and found the strongest signal to be at rs7099604 (p = 2.5 × 10−3) in intron 1 of the ADD3 gene. Moreover, expression data suggest that ADD3, but not XPNPEP1, is differentially expressed in BA patients. The role of ADD3 in biliary development is unclear, but our findings suggest that this gene may be functionally relevant for the development of BA.

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Acknowledgments

We would like to thank the patients and their families who donated their samples for this study. We also would like to acknowledge R.P. Matthews for his preliminary data on the biliary phenotype of xpnpep1 and add3a knockdown constructs in zebrafish, and M. Leyva-Vega, A. Hutchinson, and L.D. Leonard for their help in obtaining the BA samples from ChiLDREN. This work was supported by The Fred and Suzanne Biesecker Liver Center at CHOP as well as R01-DK090045 to N.B.S, U01-DK062481 to K.M.L., and R01-DK083781 to J.A.B. E.A.T. was also supported by training grant T32-HG000046.

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Authors and Affiliations

  1. Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Ellen A. Tsai

  2. Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Christopher M. Grochowski, Pierre A. Russo & Nancy B. Spinner

  3. Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kathleen M. Loomes

  4. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA

    Kathleen M. Loomes, Hakon Hakonarson & Marcella Devoto

  5. Pediatric Liver Care Center and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

    Kazuhiko Bessho & Jorge A. Bezerra

  6. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

    Kazuhiko Bessho & Jorge A. Bezerra

  7. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Hakon Hakonarson

  8. Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Hakon Hakonarson & Marcella Devoto

  9. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA

    Pierre A. Russo & Nancy B. Spinner

  10. Hepatology, Infectious Diseases Clinical Research Department, Merck Research Laboratories, North Wales, PA, USA

    Barbara A. Haber

  11. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Marcella Devoto

  12. Department of Molecular Medicine, University La Sapienza, Rome, Italy

    Marcella Devoto

Authors
  1. Ellen A. Tsai
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  2. Christopher M. Grochowski
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  3. Kathleen M. Loomes
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  4. Kazuhiko Bessho
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  5. Hakon Hakonarson
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  6. Jorge A. Bezerra
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  7. Pierre A. Russo
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  8. Barbara A. Haber
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  9. Nancy B. Spinner
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  10. Marcella Devoto
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Correspondence to Marcella Devoto.

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Tsai, E.A., Grochowski, C.M., Loomes, K.M. et al. Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia. Hum Genet 133, 235–243 (2014). https://doi.org/10.1007/s00439-013-1368-2

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  • DOI: https://doi.org/10.1007/s00439-013-1368-2

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