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  • Review Article
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Genome-wide association studies: a new window into immune-mediated diseases

Nature Reviews Immunology volume 8, pages 631–643 (2008)Cite this article

Key Points

  • Genome-wide association (GWA) studies have dramatically influenced our ability to identify genetic risk factors for complex immune-mediated diseases.

  • We provide the information necessary for immunologists to better understand the rapid advances in our knowledge of genetic variation and in the technologies to probe this variation, which have enabled GWA studies. In addition, both the analytical challenges and the strengths of these types of studies are discussed.

  • GWA studies of immune-mediated diseases, including Crohn's disease, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, have enabled the discovery of previously unknown factors that influence disease susceptibility and/or pathology.

  • Knowledge gained from these GWA studies can reveal how previously unrecognized biological pathways might contribute to disease pathogenesis. This research points toward the involvement of some pathways that are specific to one immune-mediated disease and others that are common to several different diseases.

  • Despite the success of GWA studies, several challenges lie ahead: how can we complete the mechanistic picture of how genetic variation in multiple different genes leads to disease development? How will these data impact the design of future immunology studies, and how can we apply this knowledge to clinical practice in the future?

Abstract

Given the recent explosion of genetic discoveries, 2007 is becoming known to human geneticists as the year of genome-wide association studies. In fact, more genetic risk factors for common diseases were identified in this one year than had been collectively reported before 2007. In particular, 2007 witnessed the discovery of many genes that influence susceptibility to individual immune-mediated diseases, as well as other genes that are associated with susceptibility to more than one disease. Although much work remains to be done, in this Review we discuss what effect these studies are having on our understanding of disease pathogenesis and their potential impact on future immunology studies.

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Figure 1: Schematic representation of cell-specific signalling pathways mediated by Crohn's disease susceptibility genes.
Figure 2: Interactions between innate immune cells and adaptive immune cells are central to rheumatoid arthritis and SLE pathogenesis.
Figure 3: Work flow placing candidate genes in disease-specific signalling pathways.

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References

  1. Rioux, J. D. & Abbas, A. K. Paths to understanding the genetic basis of autoimmune disease. Nature 435, 584–589 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Hirschhorn, J. N., Lohmueller, K., Byrne, E. & Hirschhorn, K. A comprehensive review of genetic association studies. Genet. Med. 4, 45–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139–144 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, D. G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. The international HapMap project. Nature 426, 789–796 (2003).

  8. Daly, M. J., Rioux, J. D., Schaffner, S. F., Hudson, T. J. & Lander, E. S. High-resolution haplotype structure in the human genome. Nature Genet. 29, 229–232 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet. 6, 95–108 (2005).

    CAS  PubMed  Google Scholar 

  11. Wang, W. Y., Barratt, B. J., Clayton, D. G. & Todd, J. A. Genome-wide association studies: theoretical and practical concerns. Nature Rev. Genet. 6, 109–118 (2005).

    CAS  PubMed  Google Scholar 

  12. Balding, D. J. A tutorial on statistical methods for population association studies. Nature Rev. Genet. 7, 781–791 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Chanock, S. J. et al. Replicating genotype-phenotype associations. Nature 447, 655–660 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Libioulle, C. et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wellcome trust case control consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  17. Nath, S. K. et al. A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus. Nature Genet. 40, 152–154 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genet. 39, 830–832 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Hafler, D. A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Plenge, R. M. et al. TRAF1–C5 as a risk locus for rheumatoid arthritis — a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. van Heel, D. A. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genet. 39, 827–829 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Zhernakova, A. et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am. J. Hum. Genet. 81, 1284–1288 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 26 June 2008 (doi: 10.1038/ng.175)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Maas, K. et al. Cutting Edge: molecular portrait of human autoimmune disease. J. Immunol. 169, 5–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Rioux, J. D. et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nature Genet. 29, 223–228 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Kanneganti, T. D., Lamkanfi, M. & Nunez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, Y. G. et al. The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity 28, 246–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Wehkamp, J., Schmid, M. & Stange, E. F. Defensins and other antimicrobial peptides in inflammatory bowel disease. Curr. Opin. Gastroenterol. 23, 370–378 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nature Rev. Immunol. 7, 767–777 (2007).

    Article  CAS  Google Scholar 

  36. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25–31 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Birmingham, C. L., Smith, A. C., Bakowski, M. A., Yoshimori, T. & Brumell, J. H. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem. 281, 11374–11383 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Taylor, G. A. IRG proteins: key mediators of interferon-regulated host resistance to intracellular pathogens. Cell. Microbiol. 9, 1099–1107 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Bekpen, C. et al. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol. 6, R92 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Ellson, C. D. et al. Neutrophils from p40phox−/− mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing. J. Exp. Med. 203, 1927–1937 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Suh, C. I. et al. The phosphoinositide-binding protein p40phox activates the NADPH oxidase during FcγIIA receptor-induced phagocytosis. J. Exp. Med. 203, 1915–1925 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rioux, J. D. et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am. J. Hum. Genet. 66, 1863–1870 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Satsangi, J. et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature Genet. 14, 199–202 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Goyette, P. et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol. 1, 131–138 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Beckly, J. B. et al. Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease. Inflamm. Bowel Dis. 14, 500–507 (2008).

    Article  PubMed  Google Scholar 

  49. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–390 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Kastelein, R. A., Hunter, C. A. & Cua, D. J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Acosta-Rodriguez, E. V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature Immunol. 8, 639–646 (2007).

    Article  CAS  Google Scholar 

  52. Annunziato, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hirota, K. et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yeo, T. W. et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann. Neurol. 61, 228–236 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gregory, S. G. et al. Interleukin 7 receptor α-chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature Genet. 39, 1083–1091 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Lundmark, F. et al. Variation in interleukin 7 receptor α-chain (IL7R) influences risk of multiple sclerosis. Nature Genet. 39, 1108–1113 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Vella, A. et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Plenge, R. M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nature Genet. 39, 1477–1482 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Tsitsikov, E. N. et al. TRAF1 is a negative regulator of TNF signaling: enhanced TNF signaling in TRAF1-deficient mice. Immunity 15, 647–657 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Chung, J. Y., Park, Y. C., Ye, H. & Wu, H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J. Cell Sci. 115, 679–688 (2002).

    CAS  PubMed  Google Scholar 

  61. Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Weinblatt, M. E. et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N. Engl. J. Med. 340, 253–259 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Vang, T. et al. Protein tyrosine phosphatases in autoimmunity. Annu. Rev. Immunol. 26, 29–55 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Criswell, L. A. et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–571 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. 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. Nature Genet. 40, 204–210 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Graham, D. S. et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nature Genet. 40, 83–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Fernando, M. M. et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS Genet. 3, e192 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Baechler, E. C. et al. Gene expression profiling in human autoimmunity. Immunol. Rev. 210, 120–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Bauer, J. W. et al. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med. 3, e491 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Graham, R. R. et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc. Natl Acad. Sci. USA 104, 6758–6763 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lim, J. et al. An essential role for talin during αMβ2-mediated phagocytosis. Mol. Biol. Cell 18, 976–985 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schymeinsky, J., Mocsai, A. & Walzog, B. Neutrophil activation via β2 integrins (CD11/CD18): molecular mechanisms and clinical implications. Thromb. Haemost. 98, 262–273 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Yokoyama, K. et al. BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP3 receptor. EMBO J. 21, 83–92 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kaplan, M. H. STAT4: a critical regulator of inflammation in vivo. Immunol. Res. 31, 231–242 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nature Genet. 40, 584–591 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genet. 40, 638–645 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Hollox, E. J. et al. Psoriasis is associated with increased β-defensin genomic copy number. Nature Genet. 40, 23–25 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Pujana, M. A. et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nature Genet. 39, 1338–1349 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Keller, M. P. et al. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res. 18, 706–716 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bottini, N., Vang, T., Cucca, F. & Mustelin, T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin. Immunol. 18, 207–213 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Rieck, M. et al. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J. Immunol. 179, 4704–4710 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Palsson-McDermott, E. M. & O'Neill, L. A. Building an immune system from nine domains. Biochem. Soc. Trans. 35, 1437–1444 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. De Jager, P. L. et al. The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus. Genes Immun. 7, 327–334 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Brand, O. J. et al. Association of the interleukin-2 receptor α (IL-2Rα)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs. Clin. Endocrinol. (Oxf.) 66, 508–512 (2007).

    CAS  Google Scholar 

  92. Graham, R. R. et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nature Genet. 38, 550–555 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Velaga, M. R. et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J. Clin. Endocrinol. Metab. 89, 5862–5865 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Smyth, D. J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genet. 38, 617–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Sutherland, A. et al. Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves' disease susceptibility. J. Clin. Endocrinol. Metab. 92, 3338–3341 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Goyette P et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal. Immunol. 1, 131–138 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Oda, K. & Kitano, H. A comprehensive map of the toll-like receptor signaling network. Mol. Syst. Biol. 2, 2006.0015 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank C. Lefebvre, A. Huett, A. Ng and C. Labbé for their help in the preparation of this manuscript. R.J.X. is supported by grants from the National Institutes of Allergy and Immunology (AI062773), National Institutes of Diabetes, Digestive and Kidney Disease (DK43,351) and CCIB development funds. J.D.R. is funded by grants from the National Institutes of Allergy and Infectious Diseases (AI065687; AI067152), from the National Institute of Diabetes and Digestive and Kidney Diseases (DK064869; DK062432) and from the Crohn's and Colitis Foundation of America (SRA512).

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Authors and Affiliations

  1. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Ramnik J. Xavier

  2. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 Bélanger Street, Montreal, H1T 1C8, Quebec, Canada

    John D. Rioux

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Correspondence to John D. Rioux.

Related links

Glossary

Causal gene

The specific gene that is responsible for disease risk conferred by a genomic region that has been identified by an association.

Linkage studies

Studies aimed at establishing linkage between a genetic marker and a disease locus. Linkage is based on the tendency of genes and genetic markers to be inherited together because of their proximity on the same chromosome.

Tag SNPs

Representative SNPs in a region of the genome with high linkage disequilibrium. Tag SNPs allow a reduction in the number of SNPs that must be genotyped while allowing the generation of the same amount of information. The HapMap Project catalogued tag SNPs in the entire genome.

Hardy–Weinberg equilibrium

A fundamental principle in genetics stating that the genotypic frequencies of a large, randomly mating population remain constant in the absence of mutation, migration, natural selection or random drift.

Penetrance

The probability, under given environmental conditions, with which a specific phenotype is expressed by individuals with a specific genotype. For example, if 50% of the people with a gene 'X' that is known to cause a disease do in fact develop the disease, then the penetrance of that gene is 0.5.

Genome-wide linkage scan

A linkage study carried out with markers located across the entire genome. Linkage studies were traditionally carried out with ∼300 markers of simple sequence-length repeats and more recently with ∼5,000 single-nucleotide polymorphisms.

Genetic markers

Genomic variants used as positional tools to find associations between specific DNA fragments and a certain phenotype or disease.

Single-nucleotide polymorphisms

(SNPs). Genomic variants in which a single base in the DNA differs from the usual base at that position. SNPs are the most common type of variation in the human genome.

Linkage disequilibrium

A situation in which alleles in a chromosomal region occur together more often than can be accounted for by chance, indicating that the alleles are in close proximity on the DNA strand and are most likely to be passed on together within a population.

Haplotype

A combination or pattern of alleles at multiple linked loci that are inherited together.

HapMap

A genetic resource created by the International HapMap Project (see the International HapMap website). The HapMap is a catalogue of common genetic variants that occur in humans. It describes what these variants are, where they occur in the genome and how they are distributed among people within populations and among populations in different parts of the world.

Genotyping

A test designed to identify the genetic constitution of an individual — that is, the alleles present at one or more specific loci.

Alleles

Alleles are alternative forms of genes that are located at a specific position on a specific chromosome. In association studies, the term allele is most commonly used to refer to one variant of a marker.

Causal variant

The specific DNA sequence that functionally gives rise to the increased risk conferred by the causal gene or genomic region identified by an association.

Copy-number variant

(CNV). A genomic variant characterized by differences in the number of copies of specific repeated DNA fragments that range from 1 kb to several Mb long. CNVs can contain entire genes and can be used as markers in association studies.

Association testing

A statistical approach that tests for association between marker or candidate gene alleles and diseases. If a correlation is observed between genotype and phenotype, there is said to be an association between the marker or allele and the disease or trait.

Replication studies

Studies designed to test (or replicate) a prior and explicit genetic hypothesis. For example, replication studies are carried out to validate the findings of a genome-wide association study, thereby discriminating false positives from true positives identified in the study.

Autophagy

A cellular process in which cytoplasmic organelles and macromolecular complexes are entrapped in double-membrane-bound vesicles for delivery to lysosomes and subsequent degradation. This process is involved in constitutive turnover of proteins and organelles and is central to cellular activities that maintain a balance between synthesis and breakdown of various proteins.

Gene desert

A large genomic segment devoid of genes. Gene deserts tend to harbour limited sequence conservation. The rare conserved region can contain transcriptional regulatory elements.

Odds ratios

Measures of relative risk, usually estimated from studies that compare patients with control subjects. In a genetic disease context, the odds ratio is defined as the ratio of the odds of having an allele or a genotype while being affected by the disease to the odds of having the same allele or a genotype while being a healthy control.

B-1 cells

B cells that express the cell-surface molecule CD5, which can bind to another B-cell-surface protein, CD72. CD5–CD72 interactions are thought to mediate B-cell–B-cell interactions. B-1 cells are mainly found in the peritoneum and have a role in T-cell-independent antibody production.

Locus

The specific position of a gene or a marker on a chromosome.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves transforming growth factor-β (TGFβ), IL-6, IL-23 or IL-21, IL-1β and the transcription factors RORγt and STAT3.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). ITAMs are protein motifs that exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases. This motif may be dually phosphorylated on tyrosines that link antigen receptors to downstream signalling molecules.

Knock-in and knockout models

Animal models generated through molecular biology experiments that aim to delete the expression of endogenous genes (knock-out) or to introduce a specific allele of a given gene (knock-in).

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Xavier, R., Rioux, J. Genome-wide association studies: a new window into immune-mediated diseases. Nat Rev Immunol 8, 631–643 (2008). https://doi.org/10.1038/nri2361

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