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  • Review Article
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Genetic architectures of seropositive and seronegative rheumatic diseases

Nature Reviews Rheumatology volume 11, pages 401–414 (2015)Cite this article

Subjects

Key Points

  • Genome-wide association studies of rheumatic diseases have revealed different shared 'genetic architectures' between seropositive and the seronegative rheumatic diseases

  • SNPs in or near BLK, IRF5, PTPN22, STAT4 and HLA class II genes are associated with many seropositive rheumatic diseases

  • Variants in or near IL23R, IL12B, ERAP1, and HLA class I genes are associated with many seronegative diseases; the ERAP1 association is limited to individuals with the disease-associated HLA class I type

  • Technological advancements in collection and analysis of high-density genetic data could lead to personalized treatment of rheumatic diseases

Abstract

Rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and some other rheumatic diseases are genetically complex, with evidence of familial clustering, but not of Mendelian inheritance. These diseases are thought to result from contributions and interactions of multiple genetic and nongenetic risk factors, which have small effects individually. Genome-wide association studies (GWAS) of large collections of data from cases and controls have revealed many genetic factors that contribute to non-Mendelian rheumatic diseases, thus providing insights into associated molecular mechanisms. This Review summarizes methods for the identification of gene variants that influence genetically complex diseases and focuses on what we have learned about the rheumatic diseases for which GWAS have been reported. Our review of the disease-associated loci identified to date reveals greater sharing of risk loci among the groups of seropositive (diseases in which specific autoantibodies are often present) or seronegative diseases than between these two groups. The nature of the shared and discordant loci suggests important similarities and differences among these diseases.

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Figure 1: LD and SNPs.
Figure 2: Imputation strategy.
Figure 3: Rheumatic disease GWAS papers published 2005–2014.
Figure 4: Genetic architecture of seropositive and seronegative rheumatic diseases.
Figure 5: ERAP1-mediated peptide handling mechanism.

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References

  1. Mahdi, H. et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis. Nat. Genet. 41, 1319–1324 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Costenbader, K. H., Gay, S., Alarcon-Riquelme, M. E., Iaccarino, L. & Doria, A. Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases? Autoimmun. Rev. 11, 604–609 (2012).

    Article  PubMed  Google Scholar 

  3. Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Manolio, T. A. Genomewide association studies and assessment of the risk of disease. N. Engl. J. Med. 363, 166–176 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Heliovaara, M., Aho, K., Aromaa, A., Knekt, P. & Reunanen, A. Smoking and risk of rheumatoid arthritis. J. Rheumatol. 20, 1830–1835 (1993).

    CAS  PubMed  Google Scholar 

  6. Katz, U. & Zandman-Goddard, G. Drug-induced lupus: an update. Autoimmun. Rev. 10, 46–50 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, M., Gao, Y., Guo, X. H. & Zhao, M. H. Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis. Nat. Rev. Nephrol. 8, 476–483 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Fumagalli, M. et al. Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution. PLoS Genet. 7, e1002355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Raj, T. et al. Common risk alleles for inflammatory diseases are targets of recent positive selection. Am. J. Hum. Genet. 92, 517–529 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lander, E. S. The new genomics: global views of biology. Science 274, 536–539 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. International HapMap Consortium. International HapMap project [online], (2015).

  13. 1000 Genomes. A deep catalog of human genetic variation [online], (2015).

  14. International HapMap Consortium. The international HapMap project. Nature 426, 789–796 (2003).

  15. Altshuler, D. M. et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Marchini, J. & Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Okada, Y. et al. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat. Genet. 44, 511–516 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Kim, K. et al. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann. Rheum. Dis. 74, e13 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Jia, X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE 8, e64683 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dilthey, A. T., Moutsianas, L., Leslie, S. & McVean, G. HLA*IMP—an integrated framework for imputing classical HLA alleles from SNP genotypes. Bioinformatics 27, 968–972 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pyo, C. W. et al. Recombinant structures expand and contract inter and intragenic diversification at the KIR locus. BMC Genomics 14, 89 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. National Human Genome Research Institute. A catalog of published genome-wide association studies. National Institutes of Health [online], (2015).

  26. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Onouchi, Y. et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat. Genet. 44, 517–521 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

    CAS  PubMed  Google Scholar 

  29. Reveille, J. D. et al. Systemic lupus erythematosus in three ethnic groups: I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. LUMINA study group. Lupus in minority populations, nature versus nurture. Arthritis Rheum. 41, 1161–1172 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Gorlova, O. et al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 7, e1002178 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lyons, P. A. et al. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367, 214–223 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mayes, M. D. et al. Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am. J. Hum. Genet. 94, 47–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Morris, D. L. et al. Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. Am. J. Hum. Genet. 91, 778–793 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Saruhan-Direskeneli, G. et al. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am. J. Hum. Genet. 93, 298–305 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Terao, C. et al. Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population. Am. J. Hum. Genet. 93, 289–297 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Remmers, E. F. et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nat. Genet. 42, 698–702 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Strange, A. et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Palm, O., Moum, B., Ongre, A. & Gran, J. T. Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study). J. Rheumatol. 29, 511–515 (2002).

    PubMed  Google Scholar 

  41. Bonfiglioli, R. et al. Frequency of HLA-B27 alleles in Brazilian patients with psoriatic arthritis. Clin. Rheumatol. 27, 709–712 (2008).

    Article  PubMed  Google Scholar 

  42. Bowness, P. et al. TH17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J. Immunol. 186, 2672–2680 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Ombrello, M. J. et al. Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc. Natl Acad. Sci. USA 111, 8867–8872 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Okada, Y. et al. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. Am. J. Hum. Genet. 95, 162–172 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Achkar, J. P. et al. Amino acid position 11 of HLA-DRβ1 is a major determinant of chromosome 6p association with ulcerative colitis. Genes Immun. 13, 245–252 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Quinton, J. F. et al. Anti-saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 42, 788–791 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Padyukov, L. et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann. Rheum. Dis. 70, 259–265 (2011).

    Article  PubMed  Google Scholar 

  48. Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Han, B. et al. Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity. Am. J. Hum. Genet. 94, 522–532 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bossini-Castillo, L. et al. A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides. Ann. Rheum. Dis. 74, e15 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Irigoyen, P. et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum. 52, 3813–3818 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Verpoort, K. N. et al. Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum. 52, 3058–3062 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Juji, T., Satake, M., Honda, Y. & Doi, Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 24, 316–319 (1984).

    Article  CAS  PubMed  Google Scholar 

  54. Haines, J. L. et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nat. Genet. 13, 469–471 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Fraussen, J., Claes, N., de Bock, L. & Somers, V. Targets of the humoral autoimmune response in multiple sclerosis. Autoimmun. Rev. 13, 1126–1137 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Baccala, R., Hoebe, K., Kono, D. H., Beutler, B. & Theofilopoulos, A. N. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat. Med. 13, 543–551 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Hall, J. C. & Rosen, A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat. Rev. Rheumatol. 6, 40–49 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kirino, Y. et al. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Haroon, N. & Inman, R. D. Endoplasmic reticulum aminopeptidases: biology and pathogenic potential. Nat. Rev. Rheumatol. 6, 461–467 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Reeves, E., Edwards, C. J., Elliott, T. & James, E. Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity. J. Immunol. 191, 35–43 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. York, I. A., Brehm, M. A., Zendzian, S., Towne, C. F. & Rock, K. L. Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance. Proc. Natl Acad. Sci. USA 103, 9202–9207 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Di Cesare, A., Di Meglio, P. & Nestle, F. O. The IL-23/TH17 axis in the immunopathogenesis of psoriasis. J. Invest. Dermatol. 129, 1339–1350 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Zaitlen, N. et al. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. PLoS Genet. 9, e1003520 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Stahl, E. A. et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat. Genet. 44, 483–489 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Casanova, J. L. & Abel, L. Revisiting Crohn's disease as a primary immunodeficiency of macrophages. J. Exp. Med. 206, 1839–1843 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Panoutsopoulou, K., Tachmazidou, I. & Zeggini, E. In search of low-frequency and rare variants affecting complex traits. Hum. Mol. Genet. 22, R16–21 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zuk, O. et al. Searching for missing heritability: designing rare variant association studies. Proc. Natl Acad. Sci. USA 111, E455–E464 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Diogo, D. et al. Rare, low-frequency, and common variants in the protein-coding sequence of biological candidate genes from GWASs contribute to risk of rheumatoid arthritis. Am. J. Hum. Genet. 92, 15–27 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kirino, Y. et al. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the Toll-like receptor 4 gene TLR4 in Behcet disease. Proc. Natl Acad. Sci. USA 110, 8134–8139 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Hunt, K. A. et al. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature 498, 232–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tang, H. et al. A large-scale screen for coding variants predisposing to psoriasis. Nat. Genet. 46, 45–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Henrichsen, C. N., Chaignat, E. & Reymond, A. Copy number variants, diseases and gene expression. Hum. Mol. Genet. 18, R1–R8 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Belot, A. et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 65, 2161–2171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Okada, Y. et al. Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene. PLoS ONE 9, e87645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhou, Q. et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N. Engl. J. Med. 370, 911–920 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Navon Elkan, P. et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N. Engl. J. Med. 370, 921–931 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Tanaka, N. et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an international multicenter collaborative Study. Arthritis Rheum. 63, 3625–3632 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Izawa, K. et al. Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99.9% statistical confidence by massively parallel sequencing. DNA Res. 19, 143–152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Omoyinmi, E. et al. Brief report: whole-exome sequencing revealing somatic NLRP3 mosaicism in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheumatol. 66, 197–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Holzelova, E. et al. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N. Engl. J. Med. 351, 1409–1418 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Lou, D. I. et al. High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing. Proc. Natl Acad. Sci. USA 110, 19872–19877 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schmitt, M. W. et al. Detection of ultra-rare mutations by next-generation sequencing. Proc. Natl Acad. Sci. USA 109, 14508–14513 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ombrello, M. J., Sikora, K. A. & Kastner, D. L. Genetics, genomics, and their relevance to pathology and therapy. Best Pract. Res. Clin. Rheumatol. 28, 175–189 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Mease, P. et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum. 63, 939–948 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. de Paoli, F., Nielsen, B., Rasmussen, F., Deleuran, B. & Sondergaard, K. Abatacept induces clinical improvement in patients with severe systemic sclerosis. Scand. J. Rheumatol 43, 342–345 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Jostins, L. & Barrett, J. C. Genetic risk prediction in complex disease. Hum. Mol. Genet. 20, R182–R188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Xie, G. et al. Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 65, 2457–2468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Khor, C. C. et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat. Genet. 43, 1241–1246 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Lee, Y. C. et al. Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat. Genet. 44, 522–525 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Lessard, C. J. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat. Genet. 45, 1284–1292 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Li, Y. et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23. Nat. Genet. 45, 1361–1365 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Radstake, T. R. et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat. Genet. 42, 426–429 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Allanore, Y. et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 7, e1002091 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Coustet, B. et al. C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis. Arthritis Rheum. 63, 2091–2096 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Martin, J. E. et al. Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up. Hum. Mol. Genet. 21, 2825–2835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zochling, J. et al. An Immunochip based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3. Arthritis Res. Ther. 16, 438 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Remmers, E. F. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yang, W. et al. Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am. J. Hum. Genet. 92, 41–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Okada, Y. et al. A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese. PLoS Genet. 8, e1002455 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yang, J. et al. ELF1 is associated with systemic lupus erythematosus in Asian populations. Hum. Mol. Genet. 20, 601–607 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Han, J. W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Kozyrev, S. V. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 40, 211–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Harley, J. B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Manjarrez-Orduno, N. et al. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat. Genet. 44, 1227–1230 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jacob, C. O. et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 106, 6256–6261 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Lessard, C. J. et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am. J. Hum. Genet. 90, 648–660 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Armstrong, D. L. et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun. 15, 347–354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ramos, P. S. et al. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet. 7, e1002406 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cunninghame Graham, D. S. et al. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet. 7, e1002341 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ramos, P. S. et al. Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus. Arthritis Rheum. 63, 2049–2057 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kim-Howard, X. et al. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Hum. Mol. Genet. 23, 1656–1668 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Molineros, J. E. et al. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genet. 9, e1003222 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kim, K. et al. Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries. Ann. Rheum. Dis. 71, 1809–1814 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Yang, W. et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 6, e1000841 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sheng, Y. J. et al. Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus. Rheumatology (Oxford) 50, 682–688 (2011).

    Article  CAS  Google Scholar 

  124. Zhang, J. et al. Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians. Hum. Mol. Genet. 23, 524–533 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Zhang, Y. et al. Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus. Hum. Mol. Genet. 24, 274–285 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Yu, Z. Y. et al. One novel susceptibility locus associate with systemic lupus erythematosus in Chinese Han population. Rheumatol. Int. 33, 2079–2083 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Deng, Y. et al. MicroRNA-3148 modulates allelic expression of Toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet. 9, e1003336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hughes, T. et al. Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21. Arthritis Rheum. 63, 1689–1697 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hinks, A. et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat. Genet. 45, 664–669 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Raychaudhuri, S. et al. Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat. Genet. 41, 1313–1318 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Suzuki, A. et al. Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat. Genet. 40, 1224–1229 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Jiang, L. et al. Novel risk Loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans. Arthritis Rheumatol. 66, 1121–1132 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. McAllister, K. et al. Identification of BACH2 and RAD51B as rheumatoid arthritis susceptibility loci in a meta-analysis of genome-wide data. Arthritis Rheum. 65, 3058–3062 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Teruel, M. et al. Association of CD247 polymorphisms with rheumatoid arthritis: a replication study and a meta-analysis. PLoS ONE 8, e68295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Myouzen, K. et al. Functional variants in NFKBIE and RTKN2 involved in activation of the NF-kB pathway are associated with rheumatoid arthritis in Japanese. PLoS Genet. 8, e1002949 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Terao, C. et al. Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis—a genome-wide study combined with immunological analyses. PLoS ONE 6, e20457 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Terao, C. et al. The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum. Mol. Genet. 20, 2680–2685 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Kochi, Y. et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat. Genet. 42, 515–519 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Anderson, C. A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246–252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yang, S. K. et al. Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 63, 80–87 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Yamazaki, K. et al. A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population. Gastroenterology 144, 781–788 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Julia, A. et al. A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300. Gut 62, 1440–1445 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Kenny, E. E. et al. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet. 8, e1002559 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Cortes, A. et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730–738 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lin, Z. et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat. Genet. 44, 73–77 (2012).

    Article  CAS  Google Scholar 

  148. Reveille, J. D. et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Capon, F. et al. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum. Mol. Genet. 17, 1938–1945 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sun, L. D. et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat. Genet. 42, 1005–1009 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nair, R. P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41, 199–204 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ellinghaus, E. et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat. Genet. 42, 991–995 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Stuart, P. E. et al. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat. Genet. 42, 1000–1004 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Cheng, H. et al. Identification of a missense variant in LNPEP that confers psoriasis risk. J. Invest. Dermatol. 134, 359–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Tsoi, L. C. et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 44, 1341–1348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ellinghaus, E. et al. Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL. J. Invest. Dermatol. 132, 1133–1140 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Apel, M. et al. Variants in RUNX3 contribute to susceptibility to psoriatic arthritis, exhibiting further common ground with ankylosing spondylitis. Arthritis Rheum. 65, 1224–1231 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Huffmeier, U. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat. Genet. 42, 996–999 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Mizuki, N. et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci. Nat. Genet. 42, 703–706 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Li, H. et al. TNFAIP3 gene polymorphisms confer risk for Behcet's disease in a Chinese Han population. Hum. Genet. 132, 293–300 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Xavier, J. M. et al. FUT2: filling the gap between genes and environment in Behcet's disease? Ann. Rheum. Dis. 74, 618–624 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Saruhan-Direskeneli, G. et al. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am. J. Hum. Genet. 93, 298–305 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Edwards, S. L., Beesley, J., French, J. D. & Dunning, A. M. Beyond GWASs: illuminating the dark road from association to function. Am. J. Hum. Genet. 93, 779–797 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–9 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. The Broad Institute [online], (2015).

  166. ENCODE. Encyclopedia of DNA elements [online], (2015).

  167. National Institutes of Health. Roadmap epigenomics project [online], (2015).

  168. Boyle, A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ward, L. D. & Kellis, M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).

    Article  CAS  PubMed  Google Scholar 

  170. 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  CAS  PubMed  PubMed Central  Google Scholar 

  171. Hu, X. et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124–130 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank M. J. Ombrello and D. L. Kastner for their comments on this manuscript. Y.K. is supported by grants from Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant No. 26713036), The Naito Memorial Foundation, The Uehara Memorial Foundation, Japan Intractable Diseases Research Foundation, Japan Rheumatic Disease Foundation, and Yokohama Foundation for Advancement of Medical Science.

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Authors and Affiliations

  1. Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan

    Yohei Kirino

  2. National Institutes of Health, National Human Genome Research Institute, Inflammatory Disease Section, 10 Center Drive, MSC 1849, Bethesda, 20892, MD, USA

    Elaine F. Remmers

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Both authors contributed equally to researching data for the article, providing substantial contribution to discussions of the content, to writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Elaine F. Remmers.

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Kirino, Y., Remmers, E. Genetic architectures of seropositive and seronegative rheumatic diseases. Nat Rev Rheumatol 11, 401–414 (2015). https://doi.org/10.1038/nrrheum.2015.41

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