Abstract: The chronic autoimmune diseases include multiple complex genetic disorders. Recently, genome-wide association studies (GWAS) have identified a large number of major loci, with many associations shared between various autoimmune diseases. These associations highlight key roles for lymphocyte activation and prioritize specific cytokine pathways and mechanisms of host-microbe recognition. Despite success in identifying loci, comprehensive models of disease pathogenesis are currently lacking. Future efforts comparing association patterns between autoimmune diseases may be particularly illustrative. New genomic technologies applied to classic genetic studies involving twins, early onset cases, and phenotypic extremes may provide key insights into developmental and gene-environment interactions in autoimmunity. The chronic autoimmune diseases include multiple complex genetic disorders. Recently, genome-wide association studies (GWAS) have identified a large number of major loci, with many associations shared between various autoimmune diseases. These associations highlight key roles for lymphocyte activation and prioritize specific cytokine pathways and mechanisms of host-microbe recognition. Despite success in identifying loci, comprehensive models of disease pathogenesis are currently lacking. Future efforts comparing association patterns between autoimmune diseases may be particularly illustrative. New genomic technologies applied to classic genetic studies involving twins, early onset cases, and phenotypic extremes may provide key insights into developmental and gene-environment interactions in autoimmunity. Autoimmune disorders are characterized by an inappropriate, ultimately excessive, inflammatory response against self, resulting in tissue destruction. Although many individuals affected by autoimmunity demonstrate multiorgan involvement, the primary end-organ target (e.g., autoimmune destruction of pancreatic islet cells in type 1 diabetes mellitus) typically drives the clinical presentation and disease definition. Evidence for both B and T lymphocyte hyper-reactivity is typically observed, with the presence of autoantibodies and genetic associations involving the major histocompatibility complex (MHC) providing the most significant association evidence for many autoimmune diseases. Most cases of autoimmunity arise in the absence of a positive family history. However, evidence that genetic factors contribute to disease pathogenesis has been provided by familial clustering in some cases, which reflects shared genetic, developmental, and environmental factors. The contribution of genetic factors is established through twin studies demonstrating higher disease concordance in monozygotic compared to dizygotic twins. In contrast to single-gene, Mendelian disorders, complex genetic disorders such as many autoimmune diseases are associated with multiple genetic loci, conferring varying effects on disease susceptibility. Within families, clustering of distinct autoimmune diseases has been reported, and this suggests the presence of shared pathogenic factors across autoimmunity. For example, a large, population-based survey demonstrated that families with a rheumatoid arthritis (RA) (Lin et al., 1998Lin J.P. Cash J.M. Doyle S.Z. Peden S. Kanik K. Amos C.I. Bale S.J. Wilder R.L. Hum. Genet. 1998; 103: 475-482Crossref PubMed Scopus (112) Google Scholar) or multiple sclerosis (MS) (Broadley et al., 2000Broadley S.A. Deans J. Sawcer S.J. Clayton D. Compston D.A. Brain. 2000; 123: 1102-1111Crossref PubMed Scopus (175) Google Scholar) proband were more likely to also manifest other autoimmune disorders. Compared to families with a single member affected by MS, the frequency of other autoimmune diseases was higher in families containing multiple members with MS, suggesting a cumulative enrichment of autoimmune susceptibility loci in these select cohorts. The application of genome-wide association studies (GWAS) to autoimmune diseases has identified a growing number of disease-associated loci. GWAS involve the genotyping of several hundred thousand single-nucleotide polymorphisms (SNPs) throughout the genome in large case-control cohorts (Manolio et al., 2009Manolio T.A. Collins F.S. Cox N.J. Goldstein D.B. Hindorff L.A. Hunter D.J. McCarthy M.I. Ramos E.M. Cardon L.R. Chakravarti A. et al.Nature. 2009; 461: 747-753Crossref PubMed Scopus (5375) Google Scholar). Because of the large number of statistical tests applied, stringent statistical thresholds are required (p value less than 5 × 10−8) to establish genome-wide evidence for association. For many associated loci, the association signals do not directly implicate a single, protein-coding gene, and the causative role for candidate genes in the region can only be speculated. A striking number of major loci have been observed to demonstrate genome-wide evidence for association in multiple, distinct autoimmune disorders (Table 1) (Barrett et al., 2008Barrett J.C. Hansoul S. Nicolae D.L. Cho J.H. Duerr R.H. Rioux J.D. Brant S.R. Silverberg M.S. Taylor K.D. Barmada M.M. et al.Nat. Genet. 2008; 40: 955-962Crossref PubMed Scopus (2027) Google Scholar, Barrett et al., 2009Barrett J.C. Clayton D.G. Concannon P. Akolkar B. Cooper J.D. Erlich H.A. Julier C. Morahan G. Nerup J. Nierras C. et al.Nat. Genet. 2009; (Published online May 10, 2009)https://doi.org/10.1038/ng.381Crossref Scopus (1206) Google Scholar, Festen et al., 2009Festen E.A. Goyette P. Scott R. Annese V. Zhernakova A. Lian J. Lefebvre C. Brant S.R. Cho J.H. 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Given the a priori epidemiological support for shared pathogenesis across autoimmune disorders, it may be argued that less stringent evidence for association would be required to establish contributions for those loci previously established in another, distinct autoimmune disease. Efforts to comprehensively genotype variation at all genome-wide significant autoimmune loci across all autoimmune diseases are ongoing. These studies will provide enormous insight into shared and distinct patterns of genetic associations across autoimmunity.Table 1Association of Genomic Loci with Autoimmune DiseasesChromosome RegionGenes of InterestaAssociation regions often encompass either no genes or multiple genes, with the precise causal gene often not definitively established.FunctionDiseasesbAS, ankylosing spondylitis; CeD, celiac disease; IBD, inflammatory bowel disease; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; T1D, type 1 diabetes mellitus.1p13PTPN22T and B cell receptor signalingRA, T1D, CD2q33CTLA4Transmits inhibitory signals to T cellsT1D, RA6p21MHCMajor histocompatibility complexMost autoimmune disorders1p13CD2/CD58Activation of T lymphocytesRA, MS1p31IL23RUnique component of the heterodimeric IL-23 receptorIBD, PS, AS1q32IL10Downregulates immune responses, including cytokines, MHC class II and costimulatory moleculesIBD, SLE, T1D4q26IL2/IL21T cell trophic growth factorsCeD, IBD, RA, T1D5q33IL12Bp40 subunit common to IL-12 and IL-23IBD, PS10p15IL2RAIL-2 receptor α chainMS, T1D6q23TNFAIP3Induced by TNF and pattern recognition receptor activation; inhibits NF-κB signalingRA, SLE, PS5q33TNIP1Interacts with TNFAIP3SLE, PS6q21PRDM1Transcriptional repressor of IFN-β; induces B cell maturationRA, SLE8p23BLKB lymphoid tyrosine kinaseSLE, RA18p11PTPN2T cell protein tyrosine phosphataseIBD, T1DGenome-wide significant association defined as p value < 5 × 10− 8.a Association regions often encompass either no genes or multiple genes, with the precise causal gene often not definitively established.b AS, ankylosing spondylitis; CeD, celiac disease; IBD, inflammatory bowel disease; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; T1D, type 1 diabetes mellitus. Open table in a new tab Genome-wide significant association defined as p value < 5 × 10− 8. Notably, many inflammatory genes implicated in autoimmunity demonstrate broad expression patterns and pleiotropic functions. However, integrative themes are emerging, implicating both established and new mechanisms of inflammation. Associated loci include a broad array of immune-associated genes involved in lymphocyte activation (receptor signaling pathways and costimulation), microbial recognition, and cytokines or cytokine receptors (Gregersen and Olsson, 2009Gregersen P.K. Olsson L.M. Annu. Rev. Immunol. 2009; 27: 363-391Crossref PubMed Scopus (229) Google Scholar). In the following sections, we highlight select genetic associations demonstrating the most significant evidence for associations in multiple autoimmune diseases. For many autoimmune disorders, the MHC represents the predominant association, highlighting its central and complex role in mediating host inflammatory responses to evolutionarily significant pathogens. The nature of antigenic responses to self- or non-self-antigens is shaped extensively by the unique coding and noncoding genetic variation of HLA alleles. Extensive allelic variation and linkage disequilibrium (nonrandom or correlated association of alleles) are observed throughout the MHC region. Recent high-density mapping in multiple autoimmune diseases demonstrated complex, multilocus effects that span the entire region, with evidence for shared and unique loci across diseases (Rioux et al., 2009Rioux J.D. Goyette P. Vyse T.J. Hammarstrom L. Fernando M.M. Green T. De Jager P.L. Foisy S. Wang J. de Bakker P.I. et al.Proc. Natl. Acad. Sci. USA. 2009; 106: 18680-18685Crossref PubMed Scopus (195) Google Scholar). After the MHC, one of the most common genetic associations across autoimmune disorders is observed at the protein tyrosine phosphatase gene PTPN22, expressed in lymphocytes. The minor tryptophan allele at Arg620Trp within PTPN22 has been associated with numerous autoimmune diseases including type 1 diabetes mellitus, RA, autoimmune thyroiditis, and systemic lupus erythematosis (SLE) (Barrett et al., 2008Barrett J.C. Hansoul S. Nicolae D.L. Cho J.H. Duerr R.H. Rioux J.D. Brant S.R. Silverberg M.S. Taylor K.D. Barmada M.M. et al.Nat. Genet. 2008; 40: 955-962Crossref PubMed Scopus (2027) Google Scholar, Bottini et al., 2004Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. MacMurray J. Meloni G.F. Lucarelli P. Pellecchia M. et al.Nat. Genet. 2004; 36: 337-338Crossref PubMed Scopus (1083) Google Scholar, WTCCC, 2007WTCCCNature. 2007; 447: 661-678Crossref PubMed Scopus (7335) Google Scholar, Criswell et al., 2005Criswell L.A. Pfeiffer K.A. Lum R.F. Gonzales B. Novitzke J. Kern M. Moser K.L. Begovich A.B. Carlton V.E. Li W. et al.Am. J. Hum. Genet. 2005; 76: 561-571Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). Interestingly, the more common arginine allele is associated with an inflammatory bowel disorder called Crohn's disease (Barrett et al., 2008Barrett J.C. Hansoul S. Nicolae D.L. Cho J.H. Duerr R.H. Rioux J.D. Brant S.R. Silverberg M.S. Taylor K.D. Barmada M.M. et al.Nat. Genet. 2008; 40: 955-962Crossref PubMed Scopus (2027) Google Scholar). The tryptophan allele results in a gain of function by the phosphatase protein relative to the arginine allele, such that B and T cell activation is inhibited; tryptophan homozygotes are characterized by a profound defect in lymphocyte receptor signaling (Rieck et al., 2007Rieck M. Arechiga A. Onengut-Gumuscu S. Greenbaum C. Concannon P. Buckner J.H. J. Immunol. 2007; 179: 4704-4710PubMed Google Scholar, Vang et al., 2005Vang T. Congia M. Macis M.D. Musumeci L. Orru V. Zavattari P. 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However, the nature (expression isoforms, cell-specific expression levels) of altered gene function resulting from disease-associated polymorphisms is largely undefined. Numerous combinations of cytokines and cytokine receptors have been associated with autoimmunity, with common and distinct patterns of association evidence reported across disorders. For example, both type 1 diabetes mellitus and MS demonstrate association to interleukin 2 receptor alpha (IL2RA), and MS also demonstrates association to interleukin 7 receptor alpha (IL7R) (Barrett et al., 2009Barrett J.C. Clayton D.G. Concannon P. Akolkar B. Cooper J.D. Erlich H.A. Julier C. Morahan G. Nerup J. Nierras C. et al.Nat. Genet. 2009; (Published online May 10, 2009)https://doi.org/10.1038/ng.381Crossref Scopus (1206) Google Scholar, Hafler et al., 2007Hafler D.A. Compston A. Sawcer S. Lander E.S. Daly M.J. De Jager P.L. de Bakker P.I. Gabriel S.B. Mirel D.B. Ivinson A.J. et al.N. Engl. J. Med. 2007; 357: 851-862Crossref PubMed Scopus (1328) Google Scholar). However, no evidence for association in either disease has been observed thus far for the shared interleukin 2 receptor gamma chain (IL2RG) required for interleukin 7 and interleukin 2 signaling. Although IL-7 has not been clearly associated with autoimmunity, associations in a gene region on chromosome 4q27 near the IL-2 and IL-21 genes have been reported in celiac disease, inflammatory bowel disease (IBD), RA, and type 1 diabetes (Barrett et al., 2009Barrett J.C. Clayton D.G. Concannon P. Akolkar B. Cooper J.D. Erlich H.A. Julier C. Morahan G. Nerup J. Nierras C. et al.Nat. Genet. 2009; (Published online May 10, 2009)https://doi.org/10.1038/ng.381Crossref Scopus (1206) Google Scholar, Festen et al., 2009Festen E.A. Goyette P. Scott R. Annese V. Zhernakova A. Lian J. Lefebvre C. Brant S.R. Cho J.H. 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However, the role of Th17-lineage cytokines in the tissues associated with these respective diseases can lead to distinct outcomes. Recent data have shown that IL-23 mediates dermal inflammation through the Th17 cytokine IL-22 (Zheng et al., 2007Zheng Y. Danilenko D.M. Valdez P. Kasman I. Eastham-Anderson J. Wu J. Ouyang W. Nature. 2007; 445: 648-651Crossref PubMed Scopus (1460) Google Scholar). IL-22 stimulation of keratinocytes leads to hyperplasia of keratinocyte layers and induction of expression of antimicrobial peptides such as β-defensin (Zenewicz and Flavell, 2008Zenewicz L.A. Flavell R.A. Eur. J. Immunol. 2008; 38: 3265-3268Crossref PubMed Scopus (84) Google Scholar). On the other hand, experimental mouse models of IBD suggest that IL-22 is protective in the intestine (Sugimoto et al., 2008Sugimoto K. Ogawa A. Mizoguchi E. Shimomura Y. Andoh A. Bhan A.K. Blumberg R.S. Xavier R.J. Mizoguchi A. J. Clin. 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The tumor necrosis factor (TNF) pathway represents a central therapeutic target across many autoimmune diseases. Multiple downstream components of TNF signaling have been associated in autoimmunity, most notably the tumor necrosis factor-inducible protein A20 (TNFAIP3), which terminates TNF- and pattern recognition receptor-induced responses of the transcription factor NF-κB. The gene region near TNFAIP3 has been associated with SLE, psoriasis, and RA (Nair et al., 2009Nair R.P. Duffin K.C. Helms C. Ding J. Stuart P.E. Goldgar D. Gudjonsson J.E. Li Y. Tejasvi T. Feng B.J. et al.Nat. Genet. 2009; 41: 199-204Crossref PubMed Scopus (989) Google Scholar, Plenge et al., 2007aPlenge R.M. Cotsapas C. Davies L. Price A.L. de Bakker P.I. Maller J. Pe'er I. Burtt N.P. Blumenstiel B. DeFelice M. et al.Nat. Genet. 2007; 39: 1477-1482Crossref PubMed Scopus (435) Google Scholar, Thomson et al., 2007Thomson W. Barton A. Ke X. Eyre S. Hinks A. Bowes J. Donn R. Symmons D. Hider S. 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More recently, uncommon polymorphisms in IFIH1, including a nonsense mutation, have been demonstrated to confer protection against developing type 1 diabetes mellitus (Nejentsev et al., 2009Nejentsev S. Walker N. Riches D. Egholm M. Todd J.A. Science. 2009; 324: 387-389Crossref PubMed Scopus (714) Google Scholar). IFIH1 recognizes RNA from picornaviruses and mediates immune activation. Importantly, infections with enteroviruses, members of the picornavirus family, are more frequent in newly diagnosed cases of type 1 diabetes mellitus and antedate the onset of disease-associated autoantibodies. Future studies testing whether wild-type IFIH1-mediated immune responses to enteroviruses induce autoreactive lymphocytes will provide key insight into its role in disease pathogenesis. If the IRF5 and IFIH1 associations highlight pathogenic roles of increased and wild-type host microbial responses, respectively, equally important is the concept that impaired, initial microbial responses may also result ultimately in increased inflammation. IBD is comprised of two major subtypes, Crohn's disease and ulcerative colitis. Both subtypes are associated with multiple IL-23 pathway genes. However, only Crohn's disease is associated with loss-of-function polymorphisms in NOD2 (pattern recognition receptor for bacterial peptidoglycan, normally resulting in NF-κB activation) and in ATG16L1-mediated autophagy. IBD is believed to result from an inappropriate host response to commensal intestinal microbes, resulting ultimately in intestinal damage from excessive inflammation (Abraham and Cho, 2009Abraham C. Cho J.H. N. Engl. J. Med. 2009; 361: 2066-2078Crossref PubMed Scopus (1869) Google Scholar). There is a functional link between pattern recognition receptors, including NOD2 and ATG16L1 (Cooney et al., 2009Cooney R. Baker J. Brain O. Danis B. Pichulik T. Allan P. Ferguson D.J. Campbell B.J. Jewell D. Simmons A. Nat. Med. 2009; 16: 90-97Crossref PubMed Scopus (774) Google Scholar, Travassos et al., 2009Travassos L.H. Carneiro L.A. Ramjeet M. Hussey S. Kim Y.G. Magalhaes J.G. Yuan L. Soares F. Chea E. Le Bourhis L. et al.Nat. Immunol. 2009; 11: 55-62Crossref PubMed Scopus (938) Google Scholar). In addition, both NOD2 and ATG16L1 are expressed in a variety of innate cells, lymphocytes, and gut epithelial Paneth cells, which secrete potent antimicrobial peptides (Abraham and Cho, 2009Abraham C. Cho J.H. N. Engl. J. Med. 2009; 361: 2066-2078Crossref PubMed Scopus (1869) Google Scholar). Therefore, in Crohn's disease, defects in first line mucosal clearance of microbes may ultimately contribute to excessive chronic inflammatory responses. Current GWAS have sampled common variation throughout the genome for disease associations (Table 2). Newer genotyping platforms that more comprehensively assay common variation will likely identify important new disease associations. GWAS in non-European populations provide important comparative insight. In addition, combining larger case-control cohorts will likely identify genomic loci of modest effect, for which smaller studies were underpowered. Identification of additional genes will provide cumulative insight into disease pathways and complex functional networks. However, for all of these complex autoimmune disorders, presently identified loci account for only a minor fraction of the predicted heritability. The identification of additional loci requiring ever larger meta-analysis cohorts using similar methodology will likely not have a significant impact on accounting for overall heritability. This would indicate that genetic variation that is not well assayed through present approaches may yet provide a significant contribution to overall disease heritability (Clayton, 2009Clayton D.G. PLoS Genet. 2009; 5: e1000540Crossref PubMed Scopus (191) Google Scholar, Manolio et al., 2009Manolio T.A. Collins F.S. Cox N.J. Goldstein D.B. Hindorff L.A. Hunter D.J. McCarthy M.I. Ramos E.M. Cardon L.R. Chakravarti A. et al.Nature. 2009; 461: 747-753Crossref PubMed Scopus (5375) Google Scholar).Table 2Emerging Approaches and Potential AdvancesApproachEstablished and Potential AdvancesGenome-wide association studiesHave identified a large number of definitive associations across autoimmunity, with many shared across autoimmune diseasesSearch for uncommon DNA variantsMay identify more penetrant alleles with larger functional effectsTranscriptome sequencingWill identify tissue-specific alternative isoforms, noncoding RNAsExpression quantitative trait loci mappingMapping DNA polymorphisms to variable RNA expressionEpigenetic analysis: chromatin modificationsMore comprehensive maps of DNA sequences modulating transcriptional regulationSequence analysis of the intestinal microbiomePotentially tractable environment covariate modulating intestinal and systemic immune responsesHumanized miceIncorporates key human immune response components in model systemsHuman immune analysesPrioritize new therapies, identify disease subtypes, and follow disease course Open table in a new tab More comprehensive cataloguing of genetic variation is ongoing, accelerated significantly by high-throughput sequencing technologies. Uncommon SNPs, and other not well assayed genetic varia