Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Pathway-based analysis of primary biliary cirrhosis genome-wide association studies

Genes & Immunity volume 14, pages 179–186 (2013)Cite this article

Subjects

Abstract

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10−4, FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Invernizzi P, Selmi C, Gershwin ME . Update on primary biliary cirrhosis. Dig Liver Dis 2010; 42: 401–408.

    Article  CAS  Google Scholar 

  2. Invernizzi P, Lleo A, Podda M . Interpreting serological tests in diagnosing autoimmune liver diseases. Semin Liver Dis 2007; 27: 161–172.

    Article  CAS  Google Scholar 

  3. Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology 2009; 49: 871–879.

    Article  CAS  Google Scholar 

  4. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ et al. Primary biliary cirrhosis. Hepatology 2009; 50: 291–308.

    Article  Google Scholar 

  5. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004; 127: 485–492.

    Article  Google Scholar 

  6. Jones DE, Watt FE, Metcalf JV, Bassendine MF, James OF . Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol 1999; 30: 402–407.

    Article  CAS  Google Scholar 

  7. Selmi C, Invernizzi P, Zuin M, Podda M, Seldin MF, Genes GershwinME . and (auto)immunity in primary biliary cirrhosis. Genes Immun 2005; 6: 543–556.

    Article  CAS  Google Scholar 

  8. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005; 42: 1194–1202.

    Article  Google Scholar 

  9. Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360: 2544–2555.

    Article  CAS  Google Scholar 

  10. Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 2010; 42: 655–657.

    Article  CAS  Google Scholar 

  11. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 2010; 42: 658–660.

    Article  CAS  Google Scholar 

  12. Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 2011; 43: 329–332.

    Article  CAS  Google Scholar 

  13. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008; 9: 356–369.

    Article  CAS  Google Scholar 

  14. Cantor RM, Lange K, Sinsheimer JS . Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet 2010; 86: 6–22.

    Article  CAS  Google Scholar 

  15. Schadt EE . Molecular networks as sensors and drivers of common human diseases. Nature 2009; 461: 218–223.

    Article  CAS  Google Scholar 

  16. Wang K, Li M, Hakonarson H . Analysing biological pathways in genome-wide association studies. Nat Rev Genet 2010; 11: 843–854.

    Article  CAS  Google Scholar 

  17. Park JH, Wacholder S, Gail MH, Peters U, Jacobs KB, Chanock SJ et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet 2010; 42: 570–575.

    Article  CAS  Google Scholar 

  18. Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One 2010; 5: e13950.

    Article  Google Scholar 

  19. Menashe I, Figueroa JD, Garcia-Closas M, Chatterjee N, Malats N, Picornell A et al. Large-scale pathway-based analysis of bladder cancer genome-wide association data from five studies of European background. PLoS One 2012; 7: e29396.

    Article  CAS  Google Scholar 

  20. Luo L, Peng G, Zhu Y, Dong H, Amos CI, Xiong M . Genome-wide gene and pathway analysis. Eur J Hum Genet 2010; 18: 1045–1053.

    Article  CAS  Google Scholar 

  21. Gui H, Li M, Sham PC, Cherny SS . Comparisons of seven algorithms for pathway analysis using the WTCCC Crohn's Disease dataset. BMC Res Notes 2011; 4: 386.

    Article  Google Scholar 

  22. Zhang K, Cui S, Chang S, Zhang L, Wang J . i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study. Nucleic Acids Res 2010; 38: W90–W95.

    Article  CAS  Google Scholar 

  23. Koyasu S . The role of PI3K in immune cells. Nat Immunol 2003; 4: 313–319.

    Article  CAS  Google Scholar 

  24. Haylock-Jacobs S, Comerford I, Bunting M, Kara E, Townley S, Klingler-Hoffmann M et al. PI3Kdelta drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation. J Autoimmun 2011; 36: 278–287.

    Article  CAS  Google Scholar 

  25. Tarasenko T, Kole HK, Chi AW, Mentink-Kane MM, Wynn TA, Bolland S . T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses. Proc Natl Acad Sci USA 2007; 104: 11382–11387.

    Article  CAS  Google Scholar 

  26. Hirschfield GM, Siminovitch KA . Toward the molecular dissection of primary biliary cirrhosis. Hepatology 2009; 50: 1347–1350.

    Article  CAS  Google Scholar 

  27. Goriely S, Cavoy R, Goldman M . Interleukin-12 family members and type I interferons in Th17-mediated inflammatory disorders. Allergy 2009; 64: 702–709.

    Article  CAS  Google Scholar 

  28. Utsugi M, Dobashi K, Ono A, Ishizuka T, Matsuzaki S, Hisada T et al. PI3K p110beta positively regulates lipopolysaccharide-induced IL-12 production in human macrophages and dendritic cells and JNK1 plays a novel role. J Immunol 2009; 182: 5225–5231.

    Article  CAS  Google Scholar 

  29. Rommel C, Camps M, Ji H . PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007; 7: 191–201.

    Article  CAS  Google Scholar 

  30. Suarez-Fueyo A, Barber DF, Martinez-Ara J, Zea-Mendoza AC, Carrera AC . Enhanced phosphoinositide 3-kinase delta activity is a frequent event in systemic lupus erythematosus that confers resistance to activation-induced T cell death. J Immunol 2011; 187: 2376–2385.

    Article  CAS  Google Scholar 

  31. Locksley RM, Killeen N, Lenardo MJ . The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104: 487–501.

    Article  CAS  Google Scholar 

  32. Jones DE . Pathogenesis of primary biliary cirrhosis. Gut 2007; 56: 1615–1624.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hochdorfer T, Kuhny M, Zorn CN, Hendriks RW, Vanhaesebroeck B, Bohnacker T et al. Activation of the PI3K pathway increases TLR-induced TNF-alpha and IL-6 but reduces IL-1beta production in mast cells. Cell Signal 2011; 23: 866–875.

    Article  Google Scholar 

  34. Frey RS, Gao X, Javaid K, Siddiqui SS, Rahman A, Malik AB . Phosphatidylinositol 3-kinase gamma signaling through protein kinase Czeta induces NADPH oxidase-mediated oxidant generation and NF-kappaB activation in endothelial cells. J Biol Chem 2006; 281: 16128–16138.

    Article  CAS  Google Scholar 

  35. Lum L, Beachy PA . The Hedgehog response network: sensors, switches, and routers. Science 2004; 304: 1755–1759.

    Article  CAS  Google Scholar 

  36. Jung Y, McCall SJ, Li YX, Diehl AM . Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology 2007; 45: 1091–1096.

    Article  Google Scholar 

  37. Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L et al. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 2008; 57: 1275–1282.

    Article  CAS  Google Scholar 

  38. Omenetti A, Syn WK, Jung Y, Francis H, Porrello A, Witek RP et al. Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology 2009; 50: 518–527.

    Article  CAS  Google Scholar 

  39. Robertson H, Kirby JA, Yip WW, Jones DE, Burt AD . Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis. Hepatology 2007; 45: 977–981.

    Article  CAS  Google Scholar 

  40. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 2008; 118: 3331–3342.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Howard S, Deroo T, Fujita Y, Itasaki N . A positive role of cadherin in Wnt/beta-catenin signalling during epithelial-mesenchymal transition. PLoS One 2011; 6: e23899.

    Article  CAS  Google Scholar 

  42. Pourebrahim R, Houtmeyers R, Ghogomu S, Janssens S, Thelie A, Tran HT et al. Transcription factor Zic2 inhibits Wnt/beta-catenin protein signaling. J Biol Chem 2011; 286: 37732–37740.

    Article  CAS  Google Scholar 

  43. Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW . Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut 2001; 49: 565–576.

    Article  CAS  Google Scholar 

  44. ENCODE Project Consortium Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA et al. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.

    Article  Google Scholar 

  45. Benjamini Y, Hochberg Y . Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995; 57: 289–300.

    Google Scholar 

  46. Wang K, Li M, Bucan M . Pathway-based approaches for analysis of genomewide association studies. Am J Hum Genet 2007; 81: 1278–1283.

    Article  CAS  Google Scholar 

  47. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH R01DK056839, NIH R01DK091823, NIH K08AR055688, Hypergenes (European Network for Genetic-Epidemiological Studies HEALTH-F4-2007-201550), Canadian Institutes for Health Research (MOP74621), the Ontario Research Fund (RE01-061), the Canadian PBC Society, a Canada Research Chair award and the Sherman Family Chair in Genomic Medicine to KAS. The authors thank C Coltescu, AL Mason, P Milkiewicz, RP Meyers, JA Odin, V Liakina, C Vincent and C Levy who assisted in recruiting cases for the Canadian-based PBC study.

Author information

Authors and Affiliations

  1. Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S P Kar, W Chen, E Lu & C I Amos

  2. School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA

    S P Kar

  3. Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California, Davis, CA, USA

    M F Seldin, P Invernizzi & M E Gershwin

  4. Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA

    M F Seldin

  5. Centre for Liver Research, Institute of Biomedical Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK

    G M Hirschfield

  6. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    G M Hirschfield

  7. Department of Medicine, Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy

    P Invernizzi

  8. Toronto Western Hospital and Department of Medicine, Liver Centre, University of Toronto, Toronto, Ontario, Canada

    J Heathcote

  9. Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy

    D Cusi

  10. Genomics and Bioinformatics Unit, Fondazione Filarete, Milan, Italy

    D Cusi

  11. Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada

    K A Siminovitch

  12. Departments of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    K A Siminovitch

  13. Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

    C I Amos

Authors
  1. S P Kar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M F Seldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G M Hirschfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Invernizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Heathcote
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Cusi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M E Gershwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K A Siminovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C I Amos
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the Italian PBC Genetics Study Group

  • Piero L Almasio
  • , Domenico Alvaro
  • , Pietro Andreone
  • , Angelo Andriulli
  • , Cristina Barlassina
  • , Antonio Benedetti
  • , Francesca Bernuzzi
  • , Ilaria Bianchi
  • , MariaConsiglia Bragazzi
  • , Maurizia Brunetto
  • , Savino Bruno
  • , Lisa Caliari
  • , Giovanni Casella
  • , Barbara Coco
  • , Agostino Colli
  • , Massimo Colombo
  • , Silvia Colombo
  • , Carmela Cursaro
  • , Lory Saveria Croce
  • , Andrea Crosignani
  • , Francesca Donato
  • , Gianfranco Elia
  • , Luca Fabris
  • , Annarosa Floreani
  • , Andrea Galli
  • , Ignazio Grattagliano
  • , Roberta Lazzari
  • , Ana Lleo
  • , Fabio Macaluso
  • , Fabio Marra
  • , Marco Marzioni
  • , Elisabetta Mascia
  • , Alberto Mattalia
  • , Renzo Montanari
  • , Lorenzo Morini
  • , Filomena Morisco
  • , Luigi Muratori
  • , Paolo Muratori
  • , Grazia Niro
  • , Antonio Picciotto
  • , Mauro Podda
  • , Piero Portincasa
  • , Daniele Prati
  • , Chiara Raggi
  • , Floriano Rosina
  • , Sonia Rossi
  • , Ilaria Sogno
  • , Giancarlo Spinzi
  • , Mario Strazzabosco
  • , Sonia Tarallo
  • , Mirko Tarocchi
  • , Claudio Tiribelli
  • , Pierluigi Toniutto
  • , Maria Vinci
  •  & Massimo Zuin

Corresponding author

Correspondence to C I Amos.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Contributors Piero L Almasio (Gastroenterology and Hepatology Unit, DiBiMIS, University of Palermo, Palermo), Domenico Alvaro (Department of Medico-Surgical Sciences and Biotechnologies, Fondazione Eleonora Lorillard Spencer Cenci, University Sapienza of Rome, Rome), Pietro Andreone (Dipartimento di Medicina Clinica, Università di Bologna, Bologna), Angelo Andriulli (IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo), Cristina Barlassina (Department of Medicine, Surgery, and Dentistry, Università degli Studi di Milano, Milan), Antonio Benedetti (Università Politecnica delle Marche, Ancona), Francesca Bernuzzi (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano), Ilaria Bianchi (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano), MariaConsiglia Bragazzi (Department of Medico-Surgical Sciences and Biotechnologies, Fondazione Eleonora Lorillard Spencer Cenci, University Sapienza of Rome, Rome), Maurizia Brunetto (Azienda Ospedaliera Universitaria Pisana, Pisa), Savino Bruno (Department of Internal Medicine, Ospedale Fatebene Fratelli e Oftalmico, Milan), Lisa Caliari (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano), Giovanni Casella (Medical Department, Desio Hospital, Desio), Barbara Coco (Azienda Ospedaliera Universitaria Pisana, Pisa), Agostino Colli (Department of Internal Medicine, AO Provincia di Lecco, Lecco), Massimo Colombo (Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan), Silvia Colombo (Treviglio Hospital, Treviglio), Carmela Cursaro (Dipartimento di Medicina Clinica, Università di Bologna, Bologna), Lory Saveria Croce (University of Trieste, and Fondazione Italiana Fegato (FIF), Trieste), Andrea Crosignani (San Paolo Hospital Medical School, Università di Milano, Milan), Francesca Donato (Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan), Gianfranco Elia (Azienda Ospedaliero-Universitaria di Parma, Parma) Luca Fabris (University of Padova, Padova), Annarosa Floreani (Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova), Andrea Galli (University of Florence, Florence), Ignazio Grattagliano (Italian College of General Practicioners, ASL Bari), Roberta Lazzari (Department of Surgical, Oncological and Gastroenterological SciencesUniversity of Padova, Padova), Ana Lleo (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano), Fabio Macaluso (Gastroenterology and Hepatology Unit, DiBiMIS, University of Palermo, Palermo), Fabio Marra (University of Florence, Florence), Marco Marzioni (Università Politecnica delle Marche, Ancona), Elisabetta Mascia (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano), Alberto Mattalia (Santa Croce Carle Hospital, Cuneo), Renzo Montanari (Ospedale di Negrar, Verona), Lorenzo Morini (Magenta Hospital, Magenta), Filomena Morisco (University of Naples, Federico II, Naples), Luigi Muratori (Department of Clinical Medicine, University of Bologna, Bologna), Paolo Muratori (Department of Clinical Medicine, University of Bologna, Bologna), Grazia Niro (IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo), Antonio Picciotto (University of Genoa, Genoa), Mauro Podda (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano) Piero Portincasa (Department of Interdisciplinary Medicine, University Medical School, Bari), Daniele Prati (Ospedale Alessandro Manzoni, Lecco, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan), Chiara Raggi (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano), Floriano Rosina (Division of Gastroenterology and Hepatology, Center for Predictive Medicine, Gradenigo Hospital, Turin), Sonia Rossi (Department of Internal Medicine, Ospedale Fatebene Fratelli e Oftalmico, Milan), Ilaria Sogno (Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano),Giancarlo Spinzi (Azienda Ospedaliera Valduce, Como), Mario Strazzabosco (Yale University, New Haven, Connecticut 06511, USA and University of Milan-Bicocca, Monza), Sonia Tarallo (Division of Gastroenterology and Hepatology, Center for Predictive Medicine, Gradenigo Hospital, Turin), Mirko Tarocchi (University of Florence, Florence), Claudio Tiribelli (University of Trieste, and Fondazione Italiana Fegato (FIF), Trieste), Pierluigi Toniutto (University of Udine, Udine), Maria Vinci (Ospedale Niguarda, Milan), Massimo Zuin (San Paolo Hospital Medical School, Università di Milano, Milan).

Supplementary Information accompanies the paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kar, S., Seldin, M., Chen, W. et al. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies. Genes Immun 14, 179–186 (2013). https://doi.org/10.1038/gene.2013.1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2013.1

Keywords

This article is cited by

Search

Advanced search

Quick links