Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis (original) (raw)

Change history

In the version of this article initially published, three authors, Paul Richardson, Ikram Nasr and Richard Aspinall, were inadvertently omitted from the list of the members of the UK PBC Consortium provided in the Supplementary Note. The error has been corrected in the supplementary information file.

References

  1. Kaplan, M.M. & Gershwin, M.E. Primary biliary cirrhosis. N. Engl. J. Med. 353, 1261–1273 (2005).
    Article CAS Google Scholar
  2. James, O.F. et al. Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology 30, 390–394 (1999).
    Article CAS Google Scholar
  3. Jones, D.E., Watt, F.E., Metcalf, J.V., Bassendine, M.F. & James, O.F. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J. Hepatol. 30, 402–407 (1999).
    Article CAS Google Scholar
  4. Donaldson, P.T. et al. HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study. Hepatology 44, 667–674 (2006).
    Article CAS Google Scholar
  5. Hirschfield, G.M. et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N. Engl. J. Med. 360, 2544–2555 (2009).
    Article CAS Google Scholar
  6. Hirschfield, G.M. et al. Variants at _IRF5_-TNPO3, 17q12–21 and MMEL1 are associated with primary biliary cirrhosis. Nat. Genet. 42, 655–657 (2010).
    Article CAS Google Scholar
  7. Liu, X. et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat. Genet. 42, 658–660 (2010).
    Article CAS Google Scholar
  8. Barrett, J.C. et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat. Genet. 41, 1330–1334 (2009).
    Article CAS Google Scholar
  9. Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).
    Article Google Scholar
  10. Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).
    Article CAS Google Scholar
  11. Li, Q. & Verma, I.M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).
    Article CAS Google Scholar
  12. Elsharkawy, A.M. et al. The NF-κB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes. J. Hepatol. 53, 519–527 (2010).
    Article CAS Google Scholar
  13. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
    Article CAS Google Scholar
  14. Zhernakova, A., van Diemen, C.C. & Wijmenga, C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat. Rev. Genet. 10, 43–55 (2009).
    Article CAS Google Scholar
  15. Jones, D.E. Pathogenesis of primary biliary cirrhosis. Gut 56, 1615–1624 (2007).
    CAS PubMed PubMed Central Google Scholar
  16. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).
    Article CAS Google Scholar
  17. Mao, T.K. et al. Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology 42, 802–808 (2005).
    Article CAS Google Scholar
  18. Vermeulen, L., Berghe, W.V., Beck, I.M., De Bosscher, K. & Haegeman, G. The versatile role of MSKs in transcriptional regulation. Trends Biochem. Sci. 34, 311–318 (2009).
    Article CAS Google Scholar
  19. Tacke, F., Luedde, T. & Trautwein, C. Inflammatory pathways in liver homeostasis and liver injury. Clin. Rev. Allergy Immunol. 36, 4–12 (2009).
    Article CAS Google Scholar
  20. Kitamura, K. et al. Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis. Lab. Invest. 82, 571–583 (2002).
    Article CAS Google Scholar
  21. Del Villar, K. & Miller, C.A. Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons. Proc. Natl. Acad. Sci. USA 101, 4210–4215 (2004).
    Article CAS Google Scholar
  22. Sleiman, P.M. et al. Variants of DENND1B associated with asthma in children. N. Engl. J. Med. 362, 36–44 (2010).
    Article CAS Google Scholar
  23. Sarma, V., Wolf, F.W., Marks, R.M., Shows, T.B. & Dixit, V.M. Cloning of a novel tumor necrosis factor-alpha-inducible primary response gene that is differentially expressed in development and capillary tube-like formation in vitro. J. Immunol. 148, 3302–3312 (1992).
    CAS PubMed Google Scholar
  24. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
    Article CAS Google Scholar
  25. Morris, J.A., Randall, J.C., Maller, J.B. & Barrett, J.C. Evoker: a visualization tool for genotype intensity data. Bioinformatics 26, 1786–1787 (2010).
    Article CAS Google Scholar
  26. Magi, R. & Morris, A.P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).
    Article Google Scholar
  27. Browning, B.L. & Browning, S.R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).
    Article CAS Google Scholar
  28. R Development Core Team. R: a language and environment for statistical computing. (R Foundation for Statistical Computing, Vienna, Austria, 2006.

Download references

Acknowledgements

The PBC sample collection was funded by the Isaac Newton Trust, the PBC Foundation and the Wellcome Trust (085925/Z/08/Z). The PBC Genetics Study is a portfolio study of the National Institute for Health Research Comprehensive Clinical Research Network (NIHR CRN, portfolio reference 5630). The WTCCC3 project is also supported by the Wellcome Trust (WT090355/A/09/Z, WT090355/B/09/Z). G.F.M. is a Clinical Research Training Fellow of the Medical Research Council (G0800460). G.F.M. is also supported by a Raymond and Beverly Sackler Studentship. C.J.H. is an NIHR Senior Research Fellow. C.A.A. is funded by the Wellcome Trust (WT91745/Z/10/Z).

We are grateful to the PBC Foundation for helping us to establish the PBC Genetics Study, for endorsing it, and for encouraging members of the Foundation to contribute samples. We thank all of the research nurses who assisted with participant recruitment in collaborating centers. We thank the staff in the NIHR CRN and Clinical Research Collaboration (CRC) Cymru for providing invaluable support. We are grateful to K. Chittock and his colleagues at Source Bioscience for their efforts. We thank O. Burren for designing the participant database and for providing information technology support. We acknowledge the Department of Twin Research and Genetic Epidemiology, King's College London for additional control genotype data, which was part-funded by a US National Institutes of Health National Eye Institute grant 1RO1EY018246 (PI, T. Young) and genotyping by the NIH Center for Inherited Disease Research (CIDR), with additional genotyping performed at the Wellcome Trust Sanger Institute. The study also received support from the NIHR comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust partnering King's College London. Finally, we thank the individuals who contributed samples used in this study.

Author information

Author notes

  1. George F Mells, James A B Floyd and Katherine I Morley: These authors contributed equally to this work.
  2. Richard N Sandford and Carl A Anderson: These authors jointly directed this work.

Authors and Affiliations

  1. Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
    George F Mells, Darren B Day, Agnes W Muriithi, Elizabeth F Wheater & Richard N Sandford
  2. Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK
    George F Mells, Muhammad F Dawwas & Graeme J Alexander
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.,
    James A B Floyd, Katherine I Morley, Christopher S Franklin, So-Youn Shin, Leena Peltonen & Carl A Anderson
  4. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Australia
    Katherine I Morley
  5. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
    Heather J Cordell
  6. Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
    Michael A Heneghan
  7. The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
    James M Neuberger
  8. Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
    Peter T Donaldson, Samantha J Ducker & David E Jones
  9. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
    Christopher J Hammond

Authors

  1. George F Mells
    You can also search for this author inPubMed Google Scholar
  2. James A B Floyd
    You can also search for this author inPubMed Google Scholar
  3. Katherine I Morley
    You can also search for this author inPubMed Google Scholar
  4. Heather J Cordell
    You can also search for this author inPubMed Google Scholar
  5. Christopher S Franklin
    You can also search for this author inPubMed Google Scholar
  6. So-Youn Shin
    You can also search for this author inPubMed Google Scholar
  7. Michael A Heneghan
    You can also search for this author inPubMed Google Scholar
  8. James M Neuberger
    You can also search for this author inPubMed Google Scholar
  9. Peter T Donaldson
    You can also search for this author inPubMed Google Scholar
  10. Darren B Day
    You can also search for this author inPubMed Google Scholar
  11. Samantha J Ducker
    You can also search for this author inPubMed Google Scholar
  12. Agnes W Muriithi
    You can also search for this author inPubMed Google Scholar
  13. Elizabeth F Wheater
    You can also search for this author inPubMed Google Scholar
  14. Christopher J Hammond
    You can also search for this author inPubMed Google Scholar
  15. Muhammad F Dawwas
    You can also search for this author inPubMed Google Scholar
  16. David E Jones
    You can also search for this author inPubMed Google Scholar
  17. Leena Peltonen
    You can also search for this author inPubMed Google Scholar
  18. Graeme J Alexander
    You can also search for this author inPubMed Google Scholar
  19. Richard N Sandford
    You can also search for this author inPubMed Google Scholar
  20. Carl A Anderson
    You can also search for this author inPubMed Google Scholar

Consortia

The UK PBC Consortium

The Wellcome Trust Case Control Consortium 3

Contributions

Study concept and design: G.F.M., H.J.C., M.A.H., J.M.N., P.T.D., the WTCCC3 management committee (see Supplementary Note), L.P., D.E.J., G.J.A., R.N.S., C.A.A.

PBC Genetics Study management: G.F.M., D.B.D., S.J.D., A.W.M., E.F.W., R.N.S.

Case ascertainment and phenotyping: G.F.M., D.B.D., S.J.D., A.W.M., E.F.W., M.F.D., The UK PBC Consortium (see Supplementary Note), D.E.J., G.J.A., R.N.S.

Control sample ascertainment: The UK Blood Service Controls group (see Supplementary Note), The 1958 Birth Cohort Controls group (see Supplementary Note), C.J.H., C.A.A.

Genotyping: The WTCCC3 DNA, Genotyping and Informatics group (see Supplementary Note).

Statistical analysis: J.A.B.F., K.I.M., H.J.C., C.S.F., S.-Y.S., The WTCCC3 data analysis group (see Supplementary Note), C.A.A.

Manuscript preparation: G.F.M., J.A.B.F., K.I.M., H.J.C., D.E.J., G.J.A., R.N.S., C.A.A.

Corresponding authors

Correspondence toRichard N Sandford or Carl A Anderson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

Supplementary information

Rights and permissions

About this article

Cite this article

Mells, G., Floyd, J., Morley, K. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat Genet 43, 329–332 (2011). https://doi.org/10.1038/ng.789

Download citation