non-MHC Loci Research Articles

Recent advances in understanding the genetic basis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a polygenic chronic autoimmune disease leading to multiple organ damage. A large heritability of up to 66% is estimated in SLE, with roughly 180 reported susceptibility loci that have been identified mostly by genome-wide association studies (GWASs) and account for approximately 30% of genetic heritability. A vast majority of risk variants reside in non-coding regions, which makes it quite challenging to interpret their functional implications in the SLE-affected immune system, suggesting the importance of understanding cell type-specific epigenetic regulation around SLE GWAS variants. The latest genetic studies have been highly fruitful as several dozens of SLE loci were newly discovered in the last few years and many loci have come to be understood in systemic approaches integrating GWAS signals with other biological resources. In this review, we summarize SLE-associated genetic variants in both the major histocompatibility complex (MHC) and non-MHC loci, examining polygenetic risk scores for SLE and their associations with clinical features. Finally, variant-driven pathogenetic functions underlying genetic associations are described, coupled with discussion about challenges and future directions in genetic studies on SLE.

176 Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine-mapping in the MHC and genomewide

We performed a GWAS of psoriasis in 2,590 cases and 1,720 controls of South Asian descent (SAS). Compared to our existing European-origin (EUR) GWAS, the effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman r = 0.78; p < 2 x 10−14). We then conducted a transethnic meta-analysis, identifying two novel non-MHC psoriasis loci (1p36.22 and 1q24.2). rs2103876 (1p36.22) is a cis-eQTL in blood for MTHFR, whose expression is positively correlated (p=4.2x10−97) with the psoriasis risk allele (T) and overexpressed in psoriatic lesional (PP) skin (p=3.06x10−23; FC =1.7). The only significant blood eQTL target for rs12046909 (1q24.2) is XCL1, a chemokine receptor ligand that is also overexpressed in PP skin (p=0.011; FC=1.95). For these two loci, the transethnic GWAS provided higher genetic resolution (mean reduction in 95% CI= 20 kb) and a reduction in the number of potential causal variants (mean = 10) than EUR alone. We explored multiple strategies to develop reference panels for accurately imputing MHC genotypes in both SAS and EUR. HLA-C*06 was the top-ranking MHC locus in both populations but was even more prominent in SAS. Transethnic modeling also substantially boosted the probability that HLA-C*06 is causal. Analysis of the extended MHC region uncovered 5 independent psoriasis loci in SAS, 14 in EUR, and 17 in transethnic, all of which map to the classical MHC. Secondary MHC signals included coding variants of HLA-C and HLA-B, but also potential regulatory variants of these two genes as well as HLA-A and several HLA class II genes, with effects on both chromatin accessibility and gene expression. This study highlights the value of transethnic meta-analysis for discovery and fine-mapping of susceptibility loci.

The Chicken MHC: Insights into Genetic Resistance, Immunity, and Inflammation Following Infectious Bronchitis Virus Infections.

The chicken immune system has provided an immense contribution to basic immunology knowledge by establishing major landmarks and discoveries that defined concepts widely used today. One of many special features on chickens is the presence of a compact and simple major histocompatibility complex (MHC). Despite its simplicity, the chicken MHC maintains the essential counterpart genes of the mammalian MHC, allowing for a strong association to be detected between the MHC and resistance or susceptibility to infectious diseases. This association has been widely studied for several poultry infectious diseases, including infectious bronchitis. In addition to the MHC and its linked genes, other non-MHC loci may play a role in the mechanisms underlying such resistance. It has been reported that innate immune responses, such as macrophage function and inflammation, might be some of the factors driving resistance or susceptibility, consequently influencing the disease outcome in an individual or a population. Information about innate immunity and genetic resistance can be helpful in developing effective preventative measures for diseases such as infectious bronchitis, to which a systemic antibody response is often not associated with disease protection. In this review, we summarize the importance of the chicken MHC in poultry disease resistance, particularly to infectious bronchitis virus (IBV) infections and the role played by innate immunity and inflammation on disease outcome. We highlight how future studies focusing on the MHC and non-MHC genes can potentially bring clarity to observed resistance in some chicken B haplotype lines.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Analysis of 47 Non-MHC Ankylosing Spondylitis Susceptibility Loci Regarding Associated Variants across Whites and Han Chinese.

To present a systematic evaluation of 47 non-MHC ankylosing spondylitis (AS) susceptibility loci that have been initially discovered through white genome-wide association studies in Han Chinese. Originally, 10,743 samples representing north and south Chinese in 4 datasets were obtained. After data quality control and imputation, metaanalysis results of 94,621 variants within 47 loci were extracted. Four ERAP1 single-nucleotide polymorphisms (SNP) and HLA-B27 tag SNP rs13202464 were used for interaction analysis. Population-attributable risk percentages of AS-associated variants were compared. Functional annotations of AS-associated variants were conducted using HaploReg, RegulomeDB, and rVarBase databases. We revealed 16 AS-associated variants with nominal evidence in Han Chinese, including rs10865331 (p = 6.30 × 10-10), rs10050860 (p = 4.09 × 10-5) and rs8070463 (p = 1.03 × 10-4). Potential susceptible SNP within these 47 loci were also identified, such as rs13024541 (2p15), rs17401719 (5q15), and rs62074054 (17q21). Epistatic interactions between 3 ERAP1 SNP (rs17401719, rs30187, and rs10050860) and HLA-B27 were confirmed. Among the 16 AS-associated variants, rs30187 showed weaker risk effect, while rs10050860 and rs12504282 seemed to attribute more risk in Han Chinese than in whites. Further genomic annotation pinpointed 35 candidate functional SNP, especially in the 2p15, ERAP1, and NPEPPS-TBKBP1 regions. Our results provided a detailed spectrum of all the reported non-MHC AS susceptibility loci in Han Chinese, which comprehensively exhibited the ethnic heterogeneity of AS susceptibility and highlighted that 2p15, ERAP1, and NPEPPS-TBKBP1 regions may play a critical role in AS pathogenesis across diverse populations.

Genetics and Functional Genomics of Spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. It encompasses several entities that share common clinical features. Most of the genetic studies in SpA have been restricted to ankylosing spondylitis (AS), the prototypical form of SpA. However, there is growing evidence of shared genetic background between all the SpA subtypes and also with some other immune-mediated diseases. The most important part of SpA heritability comes from the HLA-B27 allele in the major histocompatibility complex (MHC) that explains around 25% of the attributable heredity. Several other loci outside of the MHC have been shown to be involved in the disease. However, all these non-MHC loci explain only a small additional fraction of disease predisposition. Thus, a substantial fraction of SpA genetic basis remains poorly understood. Gene expression profiling is a complementary approach to elucidate the underlying mechanisms and pathways that drive the disease. Several expression profiling studies have been undertaken in SpA. However, results have been quite disappointing with little overlap between the studies largely due to the small sample sizes, resulting in limited power to discover small effects. In this review, we summarize current knowledge on genetic findings concerning SpA and we describe strategic approaches for identification of additional variants, with a focus on rare variants in familial forms. We also provide an overview of gene expression studies in SpA and discuss the possibilities offered by high-throughput RNA sequencing technologies, in particular in sorted cells. Finally, issues in establishing molecular mechanisms underlying genetic association hits and potential translational applications will be addressed.

P163 Accommodation in transplantation – A new model

Aim First defined as the survival and function of an organ graft in the face of otherwise lethal immunity and inflammation, accommodation might be the most common outcome of ABO-incompatible and a frequent outcome of ABO-compatible but HLA-disparate organ grafts. Accommodation was postulated to reflect an acquired resistance to injury; however, more recent work reveals a far more complex condition reflecting predisposing factors of donor and recipient origin and dynamic processes, extending over time and beyond survival and death of cells assaulted by the immune system. The overall goal of the research was to identify and test genetic determinants of accommodation. Methods We investigated donor and recipient genes and processes potentially contributing to accommodation, as it develops over periods of days, by analysis of clinical kidney transplants, murine heterotopic cardiac transplants and cell cultures. Results Human kidney transplant recipients were found commonly to exhibit B cell responses specific for the donor. The nature of these responses anticipated rejection or absence of rejection, suggesting that qualitative aspects of immunity such clonal persistence and affinity maturation, as much as presence or absence of immunity determines graft fate. Genetic loci impacting on the character of adaptive immune responses were sought and two highly polymorphic (non-MHC) loci, TNFRSF13B and TNFRSF17, were identified. Sequencing revealed distinct regions in which variants correlated with rejection versus graft well being. Mice with gene variants introduced in the locus corresponding to the human ”rejection-associated” locus predicted the quality of immune responses to model antigens and the severity of rejection of heterotopic allografts. Conclusions These findings contribute to a larger and more complex picture of biological interactions between graft and recipients that determine whether immunity eventuates in accommodation or rejection of transplants. The interactions have implications that extend beyond organ transplantation.

Primary Sj&amp;ouml;gren Syndrome: Etiology and Pathogenesis

Primary Sjögren syndrome is a chronic inflammatory disorder of the lacrimal and salivary glands resulting in oral and ocular dryness. It also has extraglandular manifestations that may affect the lung, kidneys, nervous system, and other organs. The etiology and pathogenesis of primary Sjögren syndrome are incompletely understood. A working hypothesis considers the disease to be driven by a complex interplay of environmental, genetic, and epigenetic factors. Recent genome-wide association studies confirm the previously shown contribution of major histocompatibility (MHC) locus to disease susceptibility and illuminate several non-MHC loci, which add to disease risk. New gene expression studies of peripheral blood and salivary gland tissue provide further molecular detail about the role of innate and adaptive immune pathways involved in disease mechanisms. In particular, upregulated expression of interferon and B cell–activating factor appear to play key roles in this process. Despite their drawbacks, experimental animal models continue to stimulate new lines of research that are advancing our understanding of human disease. This knowledge has been translated into new therapeutic approaches currently under evaluation in clinical trials. This review contains 5 figures, 2 tables, and 67 references. Key words: adaptive immunity, animal models, epigenetics, genome-wide association studies, innate immunity, interferon signature, lymphoma pathogenesis, nucleic acid sensing, primary Sjögren syndrome

An orthologous non-MHC locus in rats and mice is linked to CD4+ and CD8+ T-cell proportion.

CD4+ and CD8+ T cells have a central role in the immune system due to their ability to protect against infection and cancer development without targeting self. Consequently, changes in CD4+ and CD8+ T-cell homeostasis can be indicative of an array of serious illnesses, ranging from viral infections to autoimmune diseases. In addition to environmental influences, there is evidence for a genetic component regulating the proportion of CD4+ and CD8+ T cells in lymphoid organs. Indeed, identifying the genetic determinants defining the frequency of the T-cell subsets is critical as it may reveal a targetable genetic pathway to modulate CD4+ and CD8+ T-cell numbers, which could be of clinical relevance for multiple disease settings. In this study, we aim to uncover non-MHC genetic factors regulating the proportion of CD4+ and CD8+ T cells in lymphoid tissues. By investigating linkage analyses on three independent F2 cohorts, namely a rat F2 (BBDP × ACI.1U.LYP) cohort, a mouse 3A9 TCR transgenic F2 (B10.BR × NOD.H2k) cohort and a mouse F2 (C57BL/6 × FVB/N) cohort, we uncover an orthologous non-MHC locus on rat chromosome 1 and mouse chromosome 7 that is linked to T-cell proportion amongst total lymphocytes.

CTLA-4 Polymorphisms: Influence on Transplant-Related Mortality and Survival in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for a variety of hematologic diseases but is still associated with substantial morbidity and mortality. Transplant-related mortality (TRM) after HSCT depends mainly on the toxicity of the conditioning regimen, infections, and graft-versus-host disease (GVHD). Polymorphisms at major histocompatibility complex MHC) have been proven to be critical for successful allogeneic HSCT. Polymorphisms at non-MHC loci have been associated with HSCT outcome as well. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that down-regulates T-cell activation. The purpose of this study was to identify an association between CTLA-4 single nucleotide polymorphisms (SNPs) and TRM in children undergoing allogeneic HSCT.Methods: 153 donors and 153 children (median age, 11 years) with acute lymphoblastic leukemia (n=90), acute myeloid leukemia (n=58) or juvenile myelomonocytic leukemia (n=5) who underwent allogeneic HSCT in a single center were genotyped of CTLA-4 gene for rs3087243 (CT60 A/G), rs231775 (+49 A/G) and rs4553808 using TaqMan real-time polymerase chain reaction. 49 children were transplanted in first, 40 children in second and 15 in third complete remissions. 49 patients did not reach complete remission at the time of transplantation. The donor was HLA-matched unrelated in 59% of transplants and HLA-identical related in 41% of transplants. Conditioning regimen was myeloablative in all cases and based on total body irradiation in 52% of transplants or busulfan in 44% of transplants. Two forms of post-transplant immunosuppression predominated, cyclosporine A and methotrexate in 64% of transplants and cyclosporine A alone in 25% of transplants.Results: We observed a significant association between the donor´s CTLA-4 genotype of rs3087243 and TRM in children undergoing allogeneic HSCT. Genotype AG of CTLA-4 rs3087243 SNP was found in 78 donors (51%), GG in 44 donors (29%), and 31 donors were homozygous for AA (20%). 30 patients died of transplant-related causes. 16 patients died of multi-organ failure, 7 of infection, 3 of acute GVHD, 2 of chronic GVHD, and 2 of hepatic sinusoidal obstruction syndrome. Interestingly, we observed a significantly reduced TRM in children who were transplanted from a donor with the CTLA-4 genotype GG in comparison to genotype AG or AA of rs3087243 (9% versus 19% versus 36%, p=0.013). In addition, we found significant differences of event-free survival (EFS) depending on the donor´s genotype. The EFS was 64%, 46% or 32% if the patient was transplanted from a donor with CTLA-4 genotype GG, AG or AA of rs3087243, respectively (p=0.043). In multivariate analysis, CTLA-4 genotype of rs3087243 was an independent risk factor for TRM (0.021). The CTLA-4 genotypes, in either donors or recipients, had no significant impact on relapse rate, acute and chronic graft-versus host disease.Conclusions: This study provides the first evidence that the CTLA-4 polymorphisms are significant risk factors for TRM and survival in children undergoing allogeneic HSCT and should be evaluated in further trials. DisclosuresNo relevant conflicts of interest to declare.

Genomic modifiers of natural killer cells, immune responsiveness and lymphoid tissue remodeling together increase host resistance to viral infection

Abstract The MHC class I Dk molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds Dk, are required to control viral spread. The extent of Dk-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust Dk-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen.

TCR transgenic mice reveal the impact of type 1 diabetes loci on early and late disease checkpoints.

Linkage analysis studies for autoimmune diabetes have revealed multiple non-major histocompatibility complex (MHC) chromosomal regions linked to disease susceptibility. To date, more than 20 insulin-dependent diabetes (Idd) loci linked to diabetes susceptibility have been identified in NOD mice and validated via congenic breeding. Importantly, evidence suggests that Idd loci may regulate at least two pathological steps during autoimmune diabetes development, namely the onset of insulitis and the transition from insulitis to overt diabetes. Here we assess the role of various non-MHC Idd diabetes-resistance loci, which have been validated in the non-transgenic setting, on autoimmune diabetes progression in the transgenic setting. Specifically, we generated multiple Idd congenic strains in the 3A9-TCR:insHEL NOD.H2(k) transgenic model and monitored their diabetes incidence. We show that 3A9-TCR:insHEL NOD.H2(k) mice congenic for Idd3 or Idd5 display a reduction in diabetes development, whereas mice congenic for Idd9 or Idd13 exhibit an increase, in comparison with 3A9-TCR:insHEL NOD.H2(k) mice. These results suggest that the presence of the 3A9-TCR and hen egg lysosyme transgenes can offset the regulatory function of certain diabetes-resistance genetic variants contained within the Idd loci, including Idd9 and Idd13. We propose the antigen-specific 3A9-TCR:insHEL transgenic model as a useful tool for the study of the genetics of autoimmune diabetes development.

Multiple sclerosis in families: risk factors beyond known genetic polymorphisms.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by genome wide association studies and independent replication studies. A weighted genetic risk score (wGRS) was recently established using the identified MS risk loci in order to predict MS outcome including clinical and paraclinical features. Here, we present the results on a family with several affected siblings including a monozygotic triplet. The individuals were genotyped for 57 non-MHC risk loci as well as the HLA DRB1*1501 tagging SNP rs3135388 with subsequent calculation of the wGRS. Additionally, SNP array based analyses for aberrant chromosomal regions were performed for all individuals.

Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection.

The MHC class I Dk molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds Dk, are required to control viral spread. The extent of Dk-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust Dk-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen.

Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease.

Although dietary gluten is the trigger, celiac disease risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine-mapped the MHC association signal to identify additional risk factors independent of the HLA-DQ alleles and observed five novel associations that account for 18% of the genetic risk. Together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.

Annotation of functional variation within non-MHC MS susceptibility loci through bioinformatics analysis.

There is a strong and complex genetic component to multiple sclerosis (MS). In addition to variation in the major histocompatibility complex (MHC) region on chromosome 6p21.3, 110 non-MHC susceptibility variants have been identified in Northern Europeans, thus far. The majority of the MS-associated genes are immune related; however, similar to most other complex genetic diseases, the causal variants and biological processes underlying pathogenesis remain largely unknown. We created a comprehensive catalog of putative functional variants that reside within linkage disequilibrium regions of the MS-associated genic variants to guide future studies. Bioinformatics analyses were also conducted using publicly available resources to identify plausible pathological processes relevant to MS and functional hypotheses for established MS-associated variants.

No association between identified multiple sclerosis non-MHC risk loci and neuromyelitis optica.

Neuromyelitis optica (NMO) and multiple sclerosis (MS) are both autoimmune inflammatory and demyelinating disorders of the central nervous system. Recently, more than 50 MS-susceptibility single-nucleotide polymorphisms (SNPs) have been detected outside the major histocompatibility complex (MHC) region. In this study, we aimed to evaluate the association of these identified non-MHC MS risk loci with Chinese patients with NMO. Thirty-five non-MHC SNPs were selected and genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in 110 NMO patients and 332 controls from southeastern China. Among the 35 SNPs, only one, rs1800693 in the TNFRSF1A locus, was nominally associated with NMO (P = 0.045, OR = 1.550, 95% CI = 1.007-2.384). However, none of the 35 SNPs was associated with NMO after Bonferroni correction. Our results showed no association between these identified non-MHC MS risk loci and NMO, suggesting there are genetic differences in the etiology of NMO and MS.

Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans.

To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans. A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations. Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis. This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants.

Decoding multiple sclerosis: an update on genomics and future directions

A wealth of data confirms that genetic variation is an important determinant of multiple sclerosis (MS) risk. Population, family and molecular studies provide strong empirical support for a polygenic model of inheritance, driven primarily by allelic variants relatively common in the general population. The major histocompatibility complex (MHC) in chromosome 6p21.3 represents by far the strongest MS susceptibility locus genome-wide and was unambiguously identified in all studied populations. The primary signal arises from the HLA–DRB1 gene in the Class II segment of the locus, with hierarchical allelic and haplotypic effects. Independent protective signals in the telomeric Class I region of the locus have been described as well. Over the last 6 years, large multicenter DNA collections have thrived and the development of new laboratory and analytical approaches has matured at a remarkable pace, allowing pursuit of comprehensive ‘agnostic’ genome-wide association studies to identify and characterise the non-MHC genetic component of MS. Taken together, the results have provided unambiguous evidence for the association of over 100 non-MHC loci with disease susceptibility. Follow-up experiments refined some of the association signals (IL2RA and CD58), identified gene–gene interactions (HLA–DRB1/EVI5) and revealed mechanistic insights into the functional consequences of the identified gene variants, most notably an increase in the soluble to membrane-bound ratio for IL-7, IL-2 and TNF receptors and a tyrosine–protein kinase 2-mediated immune deviation. These results significantly broaden our understanding of disease pathogenesis and permit, for the first time, modeling an individual’s disease risk within the context of his or her familial history. Progress in identifying additional risk alleles is likely to be rapid in the near future. Although the effect of any given predisposing variant is modest, the possibility exists that multifaceted gene–gene and/or gene–environment interactions could substantially increase the contribution of some variants to the overall genetic risk. In addition, susceptibility genes may be subject to epigenetic modifications, which greatly increase the complexity of MS inheritance. Despite these remarkable advances, the knowledge of MS genetics remains incomplete. For example, a key but unresolved question is whether genetic variants influence disease trajectory. Ongoing efforts to fully characterize the repertoire of genes that predispose to MS and modulate its presentation is discussed. Functional characterization of even a moderate genetic effect on MS pathogenesis by a known gene or group of genes can assist in elucidating fundamental mechanisms of disease expression and yield important therapeutic opportunities.

Integrated enrichment analysis of variants and pathways in genome-wide association studies indicates central role for IL-2 signaling genes in type 1 diabetes, and cytokine signaling genes in Crohn's disease.

Pathway analyses of genome-wide association studies aggregate information over sets of related genes, such as genes in common pathways, to identify gene sets that are enriched for variants associated with disease. We develop a model-based approach to pathway analysis, and apply this approach to data from the Wellcome Trust Case Control Consortium (WTCCC) studies. Our method offers several benefits over existing approaches. First, our method not only interrogates pathways for enrichment of disease associations, but also estimates the level of enrichment, which yields a coherent way to promote variants in enriched pathways, enhancing discovery of genes underlying disease. Second, our approach allows for multiple enriched pathways, a feature that leads to novel findings in two diseases where the major histocompatibility complex (MHC) is a major determinant of disease susceptibility. Third, by modeling disease as the combined effect of multiple markers, our method automatically accounts for linkage disequilibrium among variants. Interrogation of pathways from eight pathway databases yields strong support for enriched pathways, indicating links between Crohn's disease (CD) and cytokine-driven networks that modulate immune responses; between rheumatoid arthritis (RA) and “Measles” pathway genes involved in immune responses triggered by measles infection; and between type 1 diabetes (T1D) and IL2-mediated signaling genes. Prioritizing variants in these enriched pathways yields many additional putative disease associations compared to analyses without enrichment. For CD and RA, 7 of 8 additional non-MHC associations are corroborated by other studies, providing validation for our approach. For T1D, prioritization of IL-2 signaling genes yields strong evidence for 7 additional non-MHC candidate disease loci, as well as suggestive evidence for several more. Of the 7 strongest associations, 4 are validated by other studies, and 3 (near IL-2 signaling genes RAF1, MAPK14, and FYN) constitute novel putative T1D loci for further study.