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Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci
  1. Alexandra Zhernakova1,2,3,
  2. Eli A Stahl3,4,
  3. Gosia Trynka5,
  4. Soumya Raychaudhuri4,6,7,
  5. Eleanora Festen5,
  6. Lude Franke5,8,
  7. Rudolf S N Fehrmann5,
  8. Fina A S Kurreeman1,3,4,
  9. Brian Thomson4,
  10. Namrata Gupta4,
  11. Jihane Romanos5,
  12. Ross McManus9,
  13. Anthony W Ryan9,
  14. Graham Turner9,
  15. Elaine F Remmers10,
  16. Luigi Greco11,
  17. Rene Toes1,
  18. Elvira Grandone12,
  19. Maria Cristina Mazzilli13,
  20. Anna Rybak14,
  21. Bozena Cukrowska15,
  22. Yonghong Li16,
  23. Paul I W de Bakker3,4,17,18,
  24. Peter K Gregersen19,
  25. Jane Worthington20,
  26. Katherine A Siminovitch21,
  27. Lars Klareskog22,
  28. Tom W J Huizinga1,
  29. Cisca Wijmenga5,
  30. Robert M Plenge3,4
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  3. 3Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
  4. 4Broad Institute, Cambridge, Massachusetts, USA
  5. 5Genetics Department, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands
  6. 6Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
  7. 7Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA
  8. 8Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  9. 9Department of Clinical Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland
  10. 10Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA
  11. 11European Laboratory for Food Induced Disease, University of Naples Federico II, Naples, Italy
  12. 12Unita' di Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, S Giovanni Rotondo, Foggia, Italy
  13. 13Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  14. 14Department of Gastroenterology, Hepatology and Immunology, Children's Memorial Health Institute, Warsaw, Poland
  15. 15Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland
  16. 16Celera, Alameda, California, USA
  17. 17Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  18. 18Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
  19. 19The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA
  20. 20Arthritis Research Campaign (arc) – Epidemiology Unit, The University of Manchester, Manchester, UK
  21. 21Department of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada
  22. 22Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Solna, Stockholm, Sweden

Abstract

Background and objectives Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-human leucocyte antigen (HLA) CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. The authors hypothesised that there are additional shared risk alleles, and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles.

Materials and methods The authors performed a meta-analysis of two published GWAS on CD (4533 cases and 10 750 controls) and RA (5539 cases and 17 231 controls), and genotyping the top associated single-nucleotide polymorphisms (SNPs) in independent set of 2169 CD cases and 2255 controls, and 2845 RA cases and 4944 controls. The authors used the gene-expression dataset of peripheral blood mononuclear cell of 1469 individuals to investigate the genotype-expression correlation of associated variants. The authors also analysed the results using various pathway analysis tools.

Results Above already established six shared loci, eight additional SNPs demonstrated p<5×10−8 in a combined analysis of all 50 266 samples. From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium block around the SNP. Pathway analysis tools indicate remarkable overrepresentation of T cell signalling molecules among the shared genes.

Conclusions The authors identified 14 shared CD-RA risk loci. These associations implicate antigen presentation and T cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.

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