==== Front J Pers Med J Pers Med jpm Journal of Personalized Medicine 2075-4426 MDPI 33023259 10.3390/jpm10040151 jpm-10-00151 Review The Genetics of Spondyloarthritis https://orcid.org/0000-0002-0114-2292Díaz-Peña Roberto 1* Castro-Santos Patricia 2 https://orcid.org/0000-0001-7376-7729Durán Josefina 3 Santiago Catalina 4 Lucia Alejandro 45 1 Faculty of Health Sciences, Universidad Autónoma de Chile, Talca 3460000, Chile 2 Inmunología, Centro de Investigaciones Biomédicas (CINBIO), Universidad de Vigo, 36310 Vigo, Spain; patricassan@gmail.com 3 Department of Rheumatology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 7690000, Chile; jgduran@uc.cl 4 Faculty of Sport Sciences, European University of Madrid, 28670 Madrid, Spain; catalina.santiago@universidadeuropea.es (C.S.); alejandro.lucia@universidadeuropea.es (A.L.) 5 Research Institute Hospital 12 de Octubre (‘imas12’), 28041 Madrid, Spain * Correspondence: roberto.diaz.pena@sergas.es or roberto.diaz@uautonoma.cl; Tel.: +34-981-955-073 02 10 2020 12 2020 10 4 15106 8 2020 24 9 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases with common features in terms of clinical presentation and genetic predisposition. SpA is characterized by inflammation of the spine and peripheral joints, and is also be associated with extra-articular inflammatory manifestations such as psoriasis, uveitis, or inflammatory bowel disease (IBD). The etiology of SpA is not completely understood, but it is known to have a strong genetic component dominated by the human leukocyte antigen (HLA)-B27. In the last few years, our understanding of genetic susceptibility to SpA, particularly ankylosing spondylitis (AS), has greatly improved thanks to the findings derived from powered genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays. These studies have identified many candidate genes, therefore providing new potential directions in the exploration of disease mechanisms, especially with regard to the key role of the immune system in the pathogenesis of SpA. SpA is a complex disease where genetic variability, environmental factors, and random events interact to trigger pathological pathways. The aim of this review is to summarize current findings on the genetics of SpA, some of which might help to study new treatment approaches. spondyloarthritisankylosing spondylitisgeneticsgenome-wide association studiespolymorphismethnic groupHLA-B27ERAP1KIR ==== Body 1. Introduction The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases that exhibit common features in terms of clinical presentation and genetic predisposition. SpA is characterized by inflammation of the spine and peripheral joints, and can also be associated with extra-articular inflammatory manifestations such as psoriasis, uveitis, or inflammatory bowel disease (IBD). The spectrum of SpA includes several conditions, including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), IBD-associated (or ‘enteropathic’) arthritis, juvenile spondyloarthritis, and undifferentiated SpA. Genetic variability, environmental factors, and random events can interact to trigger pathological pathways involved in SpA development [1]. With regard to genetic factors, although the etiology of SpA is not completely understood, it is known to have a strong genetic component, dominated by the human leukocyte antigen (HLA)-B27 gene. The association with HLA-B27 has been known since 1973 [2,3]. In the last few years, our understanding of genetic susceptibility to SpA, particularly AS, has considerably improved due to an increase in the statistical power of genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays [4]. The aim of this review is to summarize current state of knowledge on the genetics of SpA. Because AS is the prototype of SpA, many of the sections will focus on this condition. We also highlight potential future research directions. 2. Genetic Epidemiology of SpA It is known that SpA runs strongly within families [5]. The recurrence risk ratio of the sibling or first-degree relative of a patient has been estimated at 80 for AS and 40 for SpA as a whole [6,7]. AS is indeed highly heritable, with studies of disease recurrence conducted in twins showing a heritability for this condition of ~90% [8]. There is also high heritability with regard to the clinical manifestations of the disease [9] (e.g., 40% for radiographic disease severity and 62% for age of symptom onset). Because of the low prevalence of AS, ranging from 0.1% to 1.4% globally [10] (and thus with a very low number of twin pairs that can be assessed in research studies), it could be that the reported high values of heritability are largely due to the small sample size of most studies published in the field. In this regard, recent developments in heritability estimation have been made using SNP data from unrelated cases and controls. Thus, in the UK biobank, the heritability of AS has been estimated at 39.9%, vs. 7.4% for rheumatoid arthritis (RA), 24.1% for Crohn’s disease (CD), 18.6% for ulcerative colitis (UC), and 16.2% for psoriasis. The differences between the heritability estimations reported in twin and control-case studies suggest that there are common SNP variants involved in the pathogenesis of AS that are yet to be identified. The SNPs associated with AS would explain 27.8% of the heritability of this condition, with greatest contribution coming from the major histocompatibility complex (MHC) loci (i.e., 20.4%, vs. 7.4% for non-MHC loci) [11,12]. AS, PsA, and IBD share a common immunopathogenesis. These disorders are collectively associated with HLA class I molecules and have similar clinical features [13]. Although the exact aetiology of PsA remains unclear, cumulative evidence implicates a substantive role for genetic factors [14,15]. PsA is associated with multiple HLA molecules including HLA-B08, HLA-B27, and HLA-B38, while HLA-C06 is specific of psoriasis [16]. Besides MHC, a large number of genetic loci have been described in PsA using GWAS [17,18]. Although the association of IBD-associated arthritis with HLA is weaker compared to the other types of SpA, the role of genetics in this condition is also clear. Concordance in monozygotic twins is 50–75% for CD, although the phenotypic concordance of UC in monozygotic twins is lower (10–20%), suggesting that heritability might be less important [19]. GWAS and their subsequent meta-analyses have improved our understanding of the importance of genetic susceptibility in IBD, with more than 200 loci currently known to be potentially associated with this condition [20]. Identifying predisposing genetic polymorphisms in the context of SpA might provide clues to understanding the pathogenic mechanisms involved in this condition. 3. Major Histocompatibility Complex The genomic map of the human MHC (HLA) spans about 7.6 Mb located on the short arm of chromosome 6 (Figure 1a), and encodes core components of the immune system [21]. The classical HLA loci are labelled -A, -B, and -C (i.e., class I) and -DRB1, -DQB1, and -DPB1 (i.e., class II). HLA class I and II genes encode proteins that play a key role in the immune system by modulating responses to invading pathogens. Thus, both HLA class I and II products are involved in disease resistance and susceptibility. Specifically, the HLA region is known for its association with autoimmune diseases [21]. A hallmark of the MHC is that it contains highly polymorphic genes that encode different antigen-presenting molecules [22], with HLA class I genes showing a higher degree of polymorphism than class 2 genes (Figure 1b). The genes of the HLA class I region encode for a heavy chain of 340 amino acids (Figure 1c), whose extracellular domains (α1, α2, and α3) are encoded by exons 2, 3, and 4, respectively. Of note, the gene encoding β2-microglobulin, the light non-polymorphic chain, is located on chromosome 15. 3.1. HLA-B27 AS is one of the best examples of a disease associated with an HLA marker. This association has been demonstrated worldwide [23] and evidence for the specific role in AS of a class I surface antigen encoded by the B locus in the MHC and HLA-B27 comes from both linkage and association studies, and also from research in transgenic animal models [9]. However, identifying the mechanism(s) by which HLA-B27 participates in the pathogenesis of SpA represents a remarkable challenge. Indeed, although it has been almost 50 years since it was first described that the HLA-B27 gene contributes to SpA susceptibility [2,3], the molecular underpinnings still remain to be clearly elucidated. The prevalence of HLA-B27 varies between populations and, in general, the prevalence of AS is proportional to the frequency of HLA-B27 [24]. Thus, the prevalence of AS averages ∼8% in Europeans or North Americans, with this condition being rare among African people and Australian Aboriginals. HLA class I molecules present peptides repertoires (derived from the degradation of endogenous proteins) to CD8+ T-cells (also known as ‘cytotoxic T-lymphocytes’) and natural killer (NK) cells. Therefore, peptide binding determines the features of HLA class I molecules and the study of the pathogenic role of HLA-B27 in AS has focused on this phenomenon. More than 200 subtypes of the HLA-B27 gene have been discovered, some too rare to be investigated for disease associations. The resulting HLA-B27 peptide subtypes differ by amino acid substitutions in the exons 2 and 3 (alpha 1 and alpha 2 domains, respectively) of the peptide-binding cleft, which has six side pockets (conventionally labelled A-F). Differences in antigenic presentation can be largely interpreted in terms of the effect of polymorphisms on pocket interactions. Not all subtypes are equally distributed in world populations [23]. Thus, AS is relatively more frequently associated with HLA-B*27:05 in nearly all populations of the world, being common in Caucasians and American Indians [25]. Most of the relatively common HLA-B27 alleles (B*27:02, B*27:04, B*27:05, and B*27:07) have been associated with AS [26]: HLA-B*27:02 in Mediterranean populations, HLA-B*27:03 in sub-Saharan/Middle East populations, HLA-B*27:04 in Asian populations, and HLA-B*27:07 in Southeast Asian populations. Two allele subtypes, B*27:06 (common in Southeast Asian populations) and B*27:09 (described only in Sardinia and Southern Italy) appear to be exceptions, as they do not seem to be associated with SpA [27,28]. There are several hypotheses about the influence of the underlying mechanism of HLA-B27 and the involvement of the different B27 alleles on SpA susceptibility [26,29]. The oldest or ‘classic’ theory focuses on canonical functions of HLA-B27 in antigenic presentation. It suggests that the disease arises from the capacity of HLA-B27 to present an ‘arthritogenic peptide’ to CD8+ T-cells (Figure 2A), which ultimately leads to chronic inflammation. Due to the differential disease associations, HLA-B*27:06 and B*27:09 support the theory that a “molecular mimicry” between foreign and self-peptides may unleash a cytotoxic immune response (i.e., of CD8+ T-cells), leading to the autoimmune destruction of self-tissues [30]. As discussed later, some support the idea of the implication of an aberrant peptide presentation, with the influence of different types of HLA-B27 alleles. However, absolute binding preferences of HLA-B27 fail to entirely explain disease association [31]. An alternative mechanism might be that HLA-B27 contributes to SpA through its propensity to form HLA-B27 misfolding or heavy chain homodimerization, thereby inducing endoplasmic reticulum stress caused by the inefficient folding [32], or by interaction of B27 homodimers with receptors of innate immunity [33] (Figure 2B,C, respectively). In addition, alterations in intestinal bacterial communities (i.e., ‘dysbiosis’) have been identified in SpA [34,35], placing the microbiome as an emerging area in SpA [36]. HLA-B27-induced immunological (pro-inflammatory) changes in gut mucosa might be also implicated, with an early and sustained expansion of T-helper 17 (Th17, also known as CD4+) cells, a subset of pro-inflammatory T lymphocytes defined by their production of interleukin 17 [IL-17)] [37]. Perturbation of the interleukin (IL)-23/Th17 axis is a fundamental trigger of chronic inflammation, with Ciccia et al. showing that overexpression of IL-23, but not of IL-17, in the terminal ileum (particularly in Paneth cells) is a pivotal feature of subclinical gut inflammation in AS [38]. 3.2. Other HLA Class I Genes Discovery of non-B27 HLA associations with SpA is challenging. The huge linkage disequilibrium (LD) within the HLA region of B27 haplotypes makes it difficult to identify independent contributions of specific allelic variants. However, there is evidence suggesting that the presence of other HLA-B alleles (including B14, B38, B39, B40, and B52) might also confer greater susceptibility to AS [29]. Cortes et al. have identified other HLA-B alleles associated with AS [40] in a large study with 9069 cases and 13,578 controls of European descent. In addition to HLA-B27, several other HLA-B alleles increased disease susceptibility (i.e., the ‘risk’ alleles B*13:02, B*40:01, B*40:02, B*47:01, and HLA-B*51:01), whereas B*07:02 and B*57:01 seemed to be ‘protective’ alleles. Multiple associations of non-HLA-B27 alleles have been replicated in cohorts of patients of Asian ancestry [41] and independent associations with variants in the HLA-A and HLA-C loci have also been observed [40,42]. The prevalence of SpA is lower in Blacks and Africans than in other ethnic groups [43,44]. This could be attributable, at least partly, to a lower frequency of HLA-B27 in the former. However, the influence of HLA markers other than B27 (e.g., different HLA-B alleles) has not been investigated thoroughly in these regions. In this regard, we have conducted studies in sub-Saharan populations (i.e., Burkina Faso, Togo, and Zambia) that showed genetic evidence for an implication of HLA-B*1403 in AS [45,46]. The influence of HLA class I allotypes in AS was homogeneous in the sub-Saharan populations we studied, suggesting a common mechanism of predisposition to AS. The pathogenic behavior of B*14:03 and B*27:05 might be related to a common feature but further research is required to clarify this issue. It would be interesting to investigate the HLA-B distribution among patients with SpA in countries where the influence of B27 on the pathogenesis of this condition is less important, such as Latin American countries [47], and also to study more African countries. 3.3. Recognition by NK Cell Receptors Besides interacting with the T-cell receptor (TCR), HLA class I molecules bind to several other immunomodulatory molecules, including members of the killer immunoglobulin-like receptor (KIR, also known as CD158) family. KIR genes present a great diversity in terms of gene content and expression, and also of allelic polymorphism, encoding both activating and inhibitory receptors [48]. The presence of different combinations of KIR genes can generate inhibitory or activation signals to NK and T-cells, and the effector function is considered to result from the balance of these signals. The contribution of each KIR gene to signaling is not clear, but their relevance in SpA has been supported by different genetic studies (Table 1). KIRs are unique in terms of their diversity and of their capacity to recognize specific HLA class I allotypes. Notably, KIR3DL1 binds to the HLA-B α1 helix around residues 76–80, with specificity for all Bw4 alleles containing isoleucine at heavy chain residue 80 [49]. KIR3DL1 has been shown to recognize HLA-B27 [50], whereas in vitro-refolded B27 dimers were shown to interact with KIR3DL1 and KIR3DL2 [51]. It actually seems that both KIR receptors (KIR3DL1 and KIR3DL2) are able to bind to HLA-B27 through both the classical beta2m/heavy chain (HC) and the beta2m/free HC homodimers (HC-B27), which are independent of the sequence of the bound peptide [51]. KIR3DL2 is present on the membranes of NK and Th17 cells, and several studies have shown that HC-B27 can interact with KIR3DL2 to promote the survival and growth of both NK and Th17 cells [39,52]. This could activate the IL-23/IL-17 axis to launch the inflammatory reaction in SpA patients, but this mechanism of activation, originally derived from the HLA-B27 misfolding, needs to be characterized. KIRs and HLA class I molecules might have a modulating effect on SpA development, through a genetic imbalance between activating and inhibitory signals. This could be caused by upregulation of activation or by the loss of inhibition or by a combination thereof, with a relevant role played by specific KIR receptors. There are also studies reporting a genetic influence of KIR genes in PsA (Table 1) [71]. A positive association has been found between the activating KIR2DS1 and KIR2DS2 genes, as well as the inhibitory KIR2DL2 gene and PsA susceptibility. HLA-C1 allotypes (Ser77/Asn80) are ligands for the inhibitory receptors KIR2DL2 and KIR2DL3, as well as the activator receptor KIR2DS2, whereas HLA-C2 allotypes (Asn77/Lys80) are ligands for KIR2DL1 and KIR2DS1. Thus, the absence of ligand for inhibitory KIR (HLA-C1 for KIR2DL2) might involve a lack of inhibitory signal, which would increase susceptibility to PsA. However, despite the fact that there are promising results, to date and from a genetic perspective, most hypotheses are somewhat speculative because of the small number of samples taken into account, at least in the studies performed in PsA. 3.4. MHC Class II Region Several studies have investigated genes involved in antigenic presentation by HLA class I molecules, such as latent membrane protein 2 (LMP2) and LMP7, and transporters associated with antigen processing (TAP) [29]. These findings are interesting as they show how aberrant events in antigenic presentation may explain the pathogenesis of AS. However, the results have proven difficult to replicate. In addition, HLA class II molecules might be also involved in AS development [41]: HLA-DRB1*01:03, HLA-DRB1*11, HLA-DRB1*15:01, HLA-DQB1*02:01, HLA-DQB1*06:02. and HLADPB1*03:01. We conducted a study of high-resolution genotyping in the HLA region enrolling B27-positive patients with AS and healthy controls [72]. The results suggested that HLA-DPA1 and HLA-DPB1 alleles contributed to AS susceptibility. These findings have been replicated subsequently [40,73], providing further evidence for the possible involvement of HLA class II (DP) molecules in the development of AS. HLA-DPA1 and HLA-DPB1 forms the HLA-DP heterodimer, which functions as a receptor for processed peptides derived predominantly from membrane and extracellular proteins, and displays them to CD4+ T-cells. The strongest association has been found for an amino acid substitution in the peptide-binding cleft of HLA-DP [40], suggesting the impact on the peptide repertoire presented by HLA-DP. However, functional experiments are needed to confirm these finding 4. Genome Wide Association Studies 4.1. Current Status of Variant Discovery As mentioned above, disease-associated SNP markers explain 27.8% of the heritability of AS, with the greatest contribution (20.45) coming from MHC loci and 7.4% from non-MHC loci [11,12]. However, there are likely common SNP variants involved in AS pathogenesis that remain to be identified. In this regard, GWAS are considered to be one of the primary tools for determining genetic links to diseases [74]. Before the possibility of performing GWAS, “candidate gene studies” based on a priori hypothesis were essentially unsuccessful due to our limited understanding of the genetics of complex traits and yielded many false positive results. The emergence and development of high-throughput genotyping platforms, and analysis methods, enabled to move to the next stage, hypothesis-free GWAS. The first GWAS involving patients with AS identified two loci, located in endoplasmic reticulum aminopeptidase 1 (ERAP1) and IL23 receptor (IL23R) genes, associated with this disease [75]. Since then, there has been an exponential increase in the number of genes associated with AS (Figure 3). To date, over 100 non-MHC loci have been associated with the development of this condition [76]. The largest case–control association study in AS included genotyping of ~130,000 SNPs (Illumina Immunochip, which has incomplete genome-wide coverage) in 8726 patients with AS and 34,213 controls [11]. In this study, Ellinghaus et al. were able to identify 113 AS-associated genome-wide significant variants. Many of the genes implicated can be assigned to different categories according to their biological function and their possible role in disease (Figure 4). GWAS in SpA revealed the potential involvement of mechanisms and pathways that were previously unsuspected, particularly with regard to aminopeptidases or IL23/IL17 pathways. Three M1-aminopeptidases are associated with AS: ERAP1, ERAP2, and puromycin-sensitive aminopeptidase (NPEPPS). ERAP1 and ERAP2 cleave the peptides before their binding to HLA-B27 [77], which alters their function and might change the antigenic pool expressed by HLA-B27 molecules [78]. Moreover, genotypes of ERAP1 and ERAP2 have a considerable impact on the levels of functional enzymes in cells and on the expression of different forms of HLA-B27 on the cell surface [79]. Although the mechanism/s involved remain to be determined, ERAP-inhibition represents a potential therapeutic option [80]. There is a high percentage of genetic variants involved in the IL23 pathway that can influence AS susceptibility [75,81,82]. This has generated great interest in relation to drugs that target this pathway and their potential pharmacogenetic value. However, studies carried out to date were devoid of robustness. Only a randomized double-blind proof-of-concept study has shown an association between IL23R and ERAP1 variants, and the response of patients with AS to treatment with an IL17 inhibitor (i.e., secukinumab) [83]. Another cytokine involved in AS is tumor necrosis (TNF)α, a pro-inflammatory molecule that plays a central role in autoimmune disease pathogenesis. As with IL-23 pathway, variation in TNFα pathway genes could influence the response to (and adverse effects of) TNFα-inhibiting treatments, but the design of these studies is challenging given the multitude of environmental factors and inherent or genetic factors that can affect the drug response. The rest of loci associated to AS can be divided into the following categories: transcription factors and intergenic regions. Among transcription factors is RUNX transcription factor 3 (RUNX2) [12,84], which also has been associated with PsA [85]. RUNX3 plays a prominent role in the development and differentiation of CD8+ T-cells [86], but also has important functions in many other cell types, including chondrocytes, Th1 helper cells, dendritic cells, and NK cells [87]. Thus, understanding the pleiotropic effects of RUNX3 could be relevant to identify key aspects in the pathogenesis of AS, potentially revealing new targets for therapy. Similar to AS, the strongest genetic signal of susceptibility to psoriasis and PsA comes from the MHC region, mainly HLA-B27 and HLA-C06 [16], although there is a need for a better understanding of the relevance of HLA alleles in this condition. Three GWAS have been reported [90,91,92], identifying 13 regions associated with PsA. More recently, Stuart et al. carried out a GWAS on a very large cohort patients with PsA and unaffected controls (n = 1430 and 1417, respectively), and combined their original results with those of previously published data (yielding a total of 3061 cases and 13,670 controls) [18]. They detected 10 additional regions associated with PsA at genome-wide significance. To date, the results of GWAS and subsequent meta-analyses, as well as fine-mapping studies, have allowed identification of 50 susceptibility non-HLA genes associated with PsA [93]. Many of the genes implicated can be grouped into immune/inflammation-related genes, involving biological signalling pathways: IL23/Th17, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), janus kinase (JAK)/signal transducers and activators of transcription (STAT), and mitogen-activated protein kinase (MAPK). The most prominent genes are IL23A, TNFAIP3-interacting protein 1 (TNIP1), ERAP1, ERAP2, non-receptor tyrosine-protein kinase (TYK2), signal transducer and activator of transcription 4 (STAT4), interleukin 12 B (IL12B), RUNX3, toll-like receptor 4 (TLR4), interleukin 13 (IL13), IL23R, TRAF3 interacting protein 2 (TRAF3IP2), and protein tyrosine phosphatase, non-receptor type 22 (PTPN22)—some of them shared with other diseases, such as AS, IBD, ReA, RA, and systemic lupus erythematosus. There is a strong need for more GWAS to be conducted in patients with PsA. Genomic diversity among populations can offer new opportunities to identify genetic variants associated with AS. Recently, Bergström et al. reported a high level of genetic variation restricted by geographical regions [94]. They found an excess of previously undocumented common genetic variation private to the Americas, Southern Africa, Central Africa, and Oceania, which are usually underrepresented populations in GWAS, and absent in the rest of geographical regions (Europe, East Asia, the Middle East, or Central and South Asia). Figure 5 shows the proportion of individuals with different ancestries represented in GWAS carried out in AS. In this Figure, we have included a total of 114,306 individuals extracted from the GWAS Diversity Monitor [95]. There is a disproportionate contribution of data from African American, Afro-Caribbean, and Hispanic or Latin American populations compared to the total number of individuals included in GWAS, with Asians having a significant representation. The percent of people of European ancestry used for initial phase is higher than in replication studies (p value < 10−5), to the detriment of Asians. 4.2. Missing Heritability Although our understanding of genetic susceptibility to disease has greatly improved thanks to GWAS [74], the loci described in these studies tend to have small effect sizes, being able to explain only a modest proportion of the heritability predicted from traditional genetic epidemiology studies [96]. The case of SpA is not an exception, with only 27.8% of AS heritability being explained to date [11]. Some factors might explain this “missing heritability” [97]. First, it has been suggested that rare and ultra-rare, or low-frequency variants could explain the substantial unexplained heritability of many complex diseases. In this regard, the majority of SNPs included in GWAS are common variants, and thus SNP array-based GWAS are unable to detect ultra-rare variants associated with disease. In addition, few reports have been published that identify rare variants related to SpA. Robinson et al. analyzed the role of rare variants using whole-genome genotyping in 5040 patients with AS and 21,133 healthy controls of European descent [98]. Despite the large sample size, they were unable to identify rare coding variants with a large effect. Only one novel association achieving genome-wide significance was noted at CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) gene. By contrast, studies using a family-based design combined with next-generation sequencing technologies might be more appropriate to identify rare variants. In this regard, O’Rielly et al. showed that the presence of rare syntenic deletions in SEC16 homolog A, endoplasmic reticulum export factor (SEC16A) and MAM domain containing 4 (MAMDC4) genes increased susceptibility to Axial SpA in family members who carried the HLA-B27 allele [99]. In addition, rare variants have been identified in insulin receptor substrate 1 (IRS1) [100], ankyrin repeat and death domain containing 1B (ANKDD1B) [101], and triggering receptor expressed on myeloid cells like 2 (TREML2) [102]. However, these variants have not been robustly replicated or studied from a functional point of view. Collectively, these reports suggest that rare variants likely contribute to disease pathogenesis, but highlight the need for more studies on additional rare variants. Structural variants, such as copy number variations (CNV), deletions, and inversions, could be important contributors to complex diseases [103], but they have been poorly investigated. In SpA, a genome-wide microarray study performed in a large family with AS revealed segregation of the UDP glucuronosyltransferase family 2 member (B17UGT2B17) gene CNV among all affected family members [104]. In another study, Jung et al. detected 227 CNV regions significantly associated with the risk of AS [105]. The identification of association(s) between rare/ultra-rare or low-frequency variants, even structural variants and a given disease phenotype, should become more tractable using the GWAS approach, especially when whole-genome sequencing (WGS) will become cheaper. The great challenge in detecting complex (i.e., gene by gene and gene by environmental) interactions makes it difficult to fully explain the heritability of complex traits at the moment. Interactions between alleles at different loci, namely epistasis, could be an important component of the genetic architecture of complex traits [106]. In AS, the existence of an interaction between the ERAP1 SNP rs30187, HLA-B27, and HLAB*40:01 alleles has been demonstrated [40,89]. Similar interactions have been described for Behçet’s disease (BD) and HLA-B*51 [107], psoriasis and HLA-C*06:02 [108], and IBD and HLA-C07 [109]. All of these disorders share genetic susceptibility factors. The finding is biologically interesting, since ERAP1 trims amino terminal residues of precursor peptides to an optimal length in the endoplasmic reticulum, for HLA class I loading. HLA-B27 positive and negative AS cases differ in their association with the ERAP1 gene [89], so it is possible that ERAP1 might be involved in the generation of autoimmunogenic peptides prior to HLA-B27 assembly and peptide presentation. In addition to this finding, no gene by gene interaction study at the whole-genome level has been yet published. Like most rheumatic diseases, SpA is a multifactorial condition where many genetic factors and a high number of diverse environmental factors are involved in disease development [8]. Genetic susceptibility to SpA should be analyzed in the context of environmental risk factors, since different subsets of genes could play relevant roles depending on the risk environment. However, these environmental exposures are not easy to measure and, particularly in SpA, they have been poorly identified beyond microbial agents. In addition, because environmental exposures are not constant over time, a follow-up of SpA patients is needed. Moreover, the expression of genetic variants is modified by environmental factors and the significance of ethnicity in genetics is controversial [110]. 5. Conclusions and Future Directions GWAS approaches have increased our understanding of the role of genetic factors in the susceptibility to SpA. Yet, a remaining challenge is to identify those variants that are responsible for the unexplained (or ‘missing’) heritability. Besides the influence of gene by gene and gene by environment interactions, as well as copy number/rare variants, some authors have suggested that SNPs account for most of the ‘missing’ heritability in some health or disease traits [111,112]. In this regard, the benefits of GWAS for identifying new SNPs associated with disease phenotypes are undeniable [74] and increasing the sample size of this type of studies should facilitate the identification of new loci associated with SpA. Notably, sample sizes of over 1 million participants are being included for some conditions (e.g., insomnia [113]) and international collaborations are needed to include large patient cohorts. Efforts underway in many populations worldwide [94,114] should lay the foundation to uncover rare variants that are specific to some ethnic groups or populations, and to study their association with complex phenotypes (an example of which is SpA). On the other hand, advances in NGS techniques and in statistical approaches will allow the integration of multiple “-omics” technologies (transcriptomic, epigenomic, proteomic, metabolomic, and microbiome profiling), and thus to improve the current knowledge on SpA [115]. Approximately one third of the genetic risk in AS has been explained and, except for ERAP1, IL23R, or RUNX3, further studies are needed to confirm the associations discovered, and also to define their involvement in the disease process. Similarly, there is a need for comprehensive case-control studies analyzing the association of all KIR genes with AS, together with a complete HLA class I typing and a rigorous clinical characterization of patients—including also their response to treatment. On the other hand, a better understanding of the genetics of SpA will allow identifying genes that encode proteins representing potential therapeutic targets in SpA. In this regard, the GWAS performed up to date have revealed previously unsuspected players like ERAP1 or IL23/IL17 pathways, which have led to the development of drugs targeting aminopeptidases like ERAP1 and IL-23 pathway inhibitors, respectively. Another factor to consider, which has not been addressed in this review, is the functional mechanisms underpinning genetic associations. This is a challenge in itself, particularly in the case of SpA, where the journey is just at its beginning. Of note, the majority of disease-associated loci are located in non-coding regions of the genome, suggesting a regulatory effect of these variants on gene expression. Beyond gene identification, GWAS data have enabled a wide range of applications, including development of polygenic risk scores (PRS). The effects of individual SNP markers are limited, but collectively they provide meaningful insights into underlying pathways and contribute to models of risk-stratification for some common diseases [116]. It has been proposed that it is time to consider the inclusion of polygenic risk prediction in clinical care [117]. Rostami et al. found that a genetic risk score based on 110 susceptibility SNPs had a slightly higher ability to predict AS risk than HLA-B27 testing alone [118], albeit the improvement associated with the proposed PRS was small and of uncertain clinical value. Recently, Knevel et al. assessed the conversion of genotype information prior to clinical visit into an interpretable probability value for inflammatory arthritis, including SpA [119]. They demonstrated that genetic data might discriminate different diseases associated with similar clinical signs and symptoms. Thus, PRS are of potential use in early diagnosis or prediction of likelihood of the development of SpA, although further research is required. As more powerful GWAS are performed, future PRSs will allow for a more accurate risk stratification, with integration of familial and environmental risk factors, thereby conforming a global risk score that will improve the prediction of individual risk. In a rheumatology setting, genetic information adds value to the clinical information obtained at the initial encounter, even when serologic data are also available [120]. However, it will be necessary to ensure that all ethnic groups have access to genetic risk prediction, which will require undertaking or expanding GWAS in non-European ethnic groups. Otherwise, the clinical use of PRS might actually contribute to increase health disparities [120]. Acknowledgments We would like to acknowledge Adrián García Castillo for his work doing the graphic design. Author Contributions Conceptualization, R.D.-P. and A.L.; methodology, R.D.-P. and P.C.-S.; writing—original draft preparation, R.D.-P., P.C.-S., J.D., C.S., and A.L.; writing—review and editing, R.D.-P., P.C.-S., and A.L.; investigation, R.D.-P., P.C.-S., J.D., C.S., and A.L.; visualization, P.C.-S., J.D., and C.S.; supervision, R.D.-P. and A.L.; project administration, R.D.-P.; funding acquisition, R.D.-P. All authors have read and agreed to the published version of the manuscript. Funding This work was supported by Fondecyt grants n° 11130198. Conflicts of Interest The authors declare no conflict of interest. Figure 1 Schematic representation of the human leukocyte antigen (HLA) region (a), polymorphism in HLA class I genes (b) and structure of an HLA class I molecule (c). Figure 2 Hypotheses explaining the influence of HLA-B27 in ankylosing spondylitis (AS). According to the ‘classic’ arthritogenic peptide hypothesis, molecular mimicry between foreign and self-peptides could unleash CD8+ T-cell cross-reactivity [30], leading to AS (A). In turn, the HLA-B27 misfolding hypothesis enunciates that the accumulation of incompletely-assembled HLA-B27 molecules in the endoplasmic reticulum (ER) causes a proinflammatory unfolded protein response (UPR) that leads an increased production of interleukin (IL)-23, together with activation of T-helper (Th17) cells [26] (B). HLA-B27 has a propensity to form homodimers that can be recognized by specific receptors expressed on the surface of natural killer (NK) and CD4+ T-cells [33], increasing the expression of the proinflammatory cytokines IL17 and IL23 [39] (C). Figure 3 Genome-wide association studies in ankylosing spondylitis (AS) [11,12,75,88,89]. Figure 4 Associated genome-wide association studies (GWAS) genes grouped by categories in ankylosing spondylitis (AS). Abbreviations: ERAP, endoplasmic reticulum aminopeptidase; IL1R1, interleukin-1 receptor 1; IL2R2, interleukin-2 receptor 2; IL6R, interleukin 6 receptor; IL10, interleukin 10; IL12B, interleukin 12B; IL19, interleukin 19; IL23R, interleukin 23 receptor; JAK2, janus kinase 2; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells 1; NFKBIA, nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor alpha; NPEPPS, puromycin-sensitive amino peptidase; TNFAIP3, TNF alpha induced protein 3; TNFRSF1A, TNF receptor superfamily member 1A; TNFSF8, TNF superfamily member 8; TYK2, non-receptor tyrosine-protein kinase. Figure 5 Representation of different ethnic groups in genome-wide association studies carried out in ankylosing spondylitis. jpm-10-00151-t001_Table 1Table 1 Basic research studies showing the associations of different types of killer immunoglobulin-like receptor (KIR) with spondyloarthritis (SpA). Reference Participants, Main Assessments Conclusions [53] 366 patients with PsA and 299 controls. KIR and HLA genotyping. The activating KIR2DS1 and/or KIR2DS2 genes were more frequent in patients, showing their association with disease risk, but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, were missing. [54] 220 patients positive for psoriasis vulgaris, 75 also diagnosed as positive for PsA, and 90 controls. KIR genotyping. The activating KIR2DS1 gene was more frequent in patients with PsA, compared to those with psoriasis negative for PsA, and to unaffected controls. [55] 396 patients with psoriasis and 372 controls. Psoriasis vulgaris without joint symptoms was diagnosed in 241 patients, guttate (or ‘eruptive’) psoriasis in 80 patients, and PsA in 75 patients. KIR and HLA-C genotyping. There was a trend towards a higher KIR2DS1 gene frequency among patients with PsA. [56] Two HLA-B27–positive Caucasian populations were selected (Spain: 71 patients with AS and 105 controls; and Azores, Portugal: 55 patients with AS and 75 controls). HLA-B and KIR3DS1/3DL1 genotyping The activating KIR3DS1 gene was associated with AS compared with B27 controls, whereas the inhibitory KIR3DL1 gene was decreased in patients with AS compared with B27 controls. The effect of KIR3DL1 (protection) or KIR3DS1 gene (susceptibility) on AS might stronger when the corresponding ligand Bw4-I80 is present. [57] Two HLA-B27–positive Asian populations were selected (China: 42 patients with AS and 30 controls; and Thailand: 30 patients with AS and 16 controls) KIR3DS1, KIR2DS5, and KIR2DL5 genes were more frequent in patients with AS. The frequency of 3DL1/3DL1 and 3DL1/3DS1 genotypes was lower and higher in patients, respectively. [58] 200 patients with AS and 405 controls. KIR genotyping. No differences in KIR genotype frequencies between patients and controls. [59] 83 patients with AS and 107 controls, all HLA-B27–positive. KIR3DL1 and KIR3DS1 subtyping (genes and alleles). The frequency of the inhibitory KIR3DL1 gene was lower in patients than in B27 controls. The KIR3DL1 gene was negatively associated with AS at the expense of alleles encoding functional receptors (KIR3DL1*F) but not of KIR3DL1*004 (not functional). [60] 115 patients with AS and 119 controls, all HLA-B27–positive. KIR and HLA-C genotyping. KIR and HLA-C genotyping. The frequency of the inhibitory KIR2DL1 and KIR2DL5 gene was higher in patients than in controls. [61] 270 patients with AS and 435 controls, all HLA-B27–positive. KIR3DL1 and KIR3DS1 subtyping (genes and alleles), and HLA-B genotyping. The activating KIR3DS1*013 allele was more frequent in patients independent of the presence of the HLA-Bw4I80 epitope, whereas the presence of inhibitory allotypes such as KIR3DL1*004 demonstrated a negative association in patients in the presence of HLA-Bw4I80. [62] 35 patients with AS and 200 controls. KIR and HLA genotyping. The telomeric KIR2DL5A, KIR2DS1, and KIR3DS1 genes were more frequent in patients compared to controls. KIR3DL1/Bw4I80 and KIR2DS1/C2 compound genotypes showed association with AS. [63] 60 patients with AS and 60 controls. KIR genotyping. The activating KIR3DS1 gene was more frequent in patients than in controls. The frequency of KIR3DL1/KIR3DL1 genotype was lower in patients than in controls. [64] 110 patients with AS, 86 patients with Behçet disease, and 154 controls. KIR genotyping. Compared with controls, the frequency of the inhibitory gene KIR3DL1 was lower in patients with AS and also in those affected by uveitis. [65] 678 patients with PsA and 688 controls. KIR and HLA genotyping. The activating KIR2DS2 gene was more frequent in patients than in controls. [66] 176 patients with AS and 435 controls. KIR genotyping. The frequency of the KIR2DS1 and KIR3DS1 genes was higher in patients than in controls. [67] 200 patients with PsA and 200 controls. KIR and HLA genotyping. The inhibitory KIR2DL3 gene was more frequent in patients than in controls, whereas the frequency of the inhibitory KIR2DL5 gene was lower. [68] Successful genotyping in 392 patients with PsA, 260 patients with cutaneous psoriasis and with no arthritis, and 371 controls. KIR3DL1 subtyping (alleles). The non-functional KIR3DL1 allele was associated with psoriatic diseases (i.e., higher frequency in both types of patients compared to controls). [69] 653 patients with AS and 952 controls. KIR and HLA-C genotyping. The frequency of the inhibitory KIR2DL5 gene was lower in patients. In addition, KIR2DL5 combined with the HLA-C1/C2 heterozygous genotype showed a protective effect against AS. [70] 138 patients with ReA and 151 controls. KIR and HLA-C genotyping. The inhibitory KIR2DL2 and KIR2DL5 genes were less frequent in patients than in controls. The activating KIR2DS1 alone or in combination with the HLA-C1C1 genotype was associated with susceptibility to ReA, whereas KIR2DL2 in combination with the HLA-C1 ligand was associated with protection against ReA. Abbreviations: HLA, Human Leukocyte Antigen; PsA, psoriatic arthritis; ReA, reactive arthritis. ==== Refs References 1. Sparks J.A. Costenbader K.H. Genetics, environment, and gene-environment interactions in the development of systemic rheumatic diseases Rheum. Dis. Clin. N. Am. 2014 40 637 657 10.1016/j.rdc.2014.07.005 25437282 2. Schlosstein L. Terasaki P.I. Bluestone R. Pearson C.M. High Association of an HL-A Antigen, W27, with Ankylosing Spondylitis N. Engl. J. Med. 1973 288 704 706 10.1056/NEJM197304052881403 4688372 3. Caffrey M.F.P. James D.C.O. Human lymphocyte antigen association in ankylosing spondylitis Nature 1973 242 121 10.1038/242121a0 4694299 4. Li Z. Brown M.A. Progress of genome-wide association studies of ankylosing spondylitis Clin. Transl. Immunol. 2017 6 e163 10.1038/cti.2017.49 5. De Blecourt J.J. Polman A. de Blécourt-Meindersma T. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis Ann. Rheum. Dis. 1961 20 215 220 10.1136/ard.20.3.215 13869952 6. Brown M.A. Laval S.H. Brophy S. Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis Ann. Rheum. Dis. 2000 59 883 886 10.1136/ard.59.11.883 11053066 7. Dernis E. Said-Nahal R. D’agostino M.A. Aegerter P. Dougados M. Breban M. Recurrence of spondylarthropathy among firstdegree relatives of patients: A systematic crosssectional Study Ann. Rheum. Dis. 2009 68 502 507 10.1136/ard.2008.089599 18413442 8. Brown M.A. Kennedy L.G. MacGregor A.J. Darke C. Duncan E. Shatford J.L. Taylor A. Calin A. Wordsworth P. Susceptibility to ankylosing spondylitis in twins: The role of genes, HLA, and the environment Arthritis Rheum. 1997 40 1823 1828 10.1002/art.1780401015 9336417 9. Thomas G.P. Brown M.A. Genetics and genomics of ankylosing spondylitis Immunol. Rev. 2010 233 162 180 10.1111/j.0105-2896.2009.00852.x 20192999 10. Dean L.E. Jones G.T. Macdonald A.G. Downham C. Sturrock R.D. Macfarlane G.J. Global prevalence of ankylosing spondylitis Rheumatology 2014 53 650 657 10.1093/rheumatology/ket387 24324212 11. Ellinghaus D. Jostins L. Spain S.L. Cortes A. Bethune J. Han B. Park Y.R. Raychaudhuri S. Pouget J.G. Hübenthal M. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci Nat. Genet. 2016 48 510 518 10.1038/ng.3528 26974007 12. Cortes A. Hadler J. Pointon J.P. Robinson P.C. Karaderi T. Leo P. Cremin K. Pryce K. Harris J. Lee S. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci Nat. Genet. 2013 45 730 738 23749187 13. McGonagle D. Aydin S.Z. Gül A. Mahr A. Direskeneli H. ’MHC-I-opathy’—Unified concept for spondyloarthritis and Behçet disease Nat. Rev. Rheumatol. 2015 11 731 740 10.1038/nrrheum.2015.147 26526644 14. Myers A. Kay L.J. Lynch S.A. Walker D.J. Recurrence risk for psoriasis and psoriatic arthritis within sibships Rheumatology 2005 44 773 776 10.1093/rheumatology/keh589 15757963 15. Chandran V. Schentag C.T. Brockbank J.E. Pellett F.J. Shanmugarajah S. Toloza S.M.A. Rahman P. Gladman D.D. Familial aggregation of psoriatic arthritis Ann. Rheum. Dis. 2009 68 664 667 10.1136/ard.2008.089367 18524791 16. Winchester R. Minevich G. Steshenko V. Kirby B. Kane D. Greenberg D.A. FitzGerald O. HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype Arthritis Rheum. 2012 64 1134 1144 10.1002/art.33415 22006066 17. Stuart P.E. Nair R.P. ELinghaus E. Ding J. Tejasvi T. GudjonSon J.E. Li Y. Weidinger S. Eberlein B. Gieger C. Genome-wide asociation analysis identifies three psoriasis susceptibility loci Nat. Genet. 2010 42 1000 1004 10.1038/ng.693 20953189 18. Stuart P.E. Nair R.P. Tsoi L.C. Tejasvi T. Das S. Kang H.M. Ellinghaus E. Chandran V. Callis-Duffin K. Ike R. Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture Am. J. Hum. Genet. 2015 97 816 836 10.1016/j.ajhg.2015.10.019 26626624 19. Halme L. Paavola-Sakki P. Turunen U. Lappalainen M. Färkkilä M. Kontula K. Family and twin studies in inflammatory bowel disease World J. Gastroenterol. 2006 12 3668 3672 10.3748/wjg.v12.i23.3668 16773682 20. Annese V. Genetics and epigenetics of IBD Pharmacol. Res. 2020 159 104892 10.1016/j.phrs.2020.104892 32464322 21. Trowsdale J. Knight J.C. Major histocompatibility complex genomics and human disease Annu. Rev. Genom. Hum. Genet. 2013 14 301 323 10.1146/annurev-genom-091212-153455 23875801 22. Robinson J. Guethlein L.A. Cereb N. Yang S.Y. Norman P.J. Marsh S.G.E. Parham P. Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles PLoS Genet. 2017 13 e1006862 10.1371/journal.pgen.1006862 28650991 23. Gonzalez-Roces S. Alvarez M.V. Gonzalez S. Dieye A. Makni H. Woodfield D.G. Housan L. Konenkov V. Abbadi M.C. Grunnet N. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis Tissue Antigens 1997 49 116 123 10.1111/j.1399-0039.1997.tb02724.x 9062966 24. Khan M.A. Remarkable polymorphism of HLA-B27: An ongoing saga Curr. Rheumatol. Rep. 2010 12 337 341 10.1007/s11926-010-0126-x 20683684 25. Reveille J.D. Maganti R.M. Subtypes of HLA-B27: History and implications in the pathogenesis of ankylosing spondylitis Adv. Exp. Med. Biol. 2009 649 159 176 19731628 26. Colbert R.A. Navid F. Gill T. The role of HLA-B*27 in spondyloarthritis Best Pract. Res. Clin. Rheumatol. 2017 31 797 815 10.1016/j.berh.2018.07.012 30509441 27. López-Larrea C. Sujirachato K. Mehra N.K. Chiewsilp P. Isarangkura D. Kanga U. Dominguez O. Coto E. Penã M. Setién F. HLA-B27 subtypes in Asian patients with ankylosing spondylitis Evidence for new associations Tissue Antigens 1995 45 169 176 10.1111/j.1399-0039.1995.tb02436.x 7761976 28. Paladini F. Taccari E. Fiorillo M.T. Cauli A. Passiu G. Mathieu A. Punzi L. Lapadula G. Scarpa R. Sorrentino R. Distribution of HLA-B27 subtypes in Sardinia and continental Italy and their association with spondylarthropathies Arthritis Rheum. 2005 52 3319 3321 10.1002/art.21308 16200572 29. Benjamin R. Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis Immunol. Today 1990 11 137 142 10.1016/0167-5699(90)90051-A 2187471 30. Kollnberger S. Bowness P. The role of B27 heavy chain dimer immune receptor interactions in spondyloarthritis Adv. Exp. Med. Biol. 2009 649 277 285 19731637 31. Bowness P. Ridley A. Shaw J. Chan A.T. Wong-Baeza I. Fleming M. Cummings F. McMichael A. Kollnberger S. Th17 Cells Expressing KIR3DL2+ and Responsive to HLA-B27 Homodimers Are Increased in Ankylosing Spondylitis J. Immunol. 2011 186 2672 2680 10.4049/jimmunol.1002653 21248258 32. Díaz-Peña R. López-Vázquez A. López-Larrea C. Old and new HLA associations with ankylosing spondylitis Tissue Antigens 2012 80 205 213 10.1111/j.1399-0039.2012.01944.x 22881057 33. Schittenhelm R.B. Sian T.C.C.L.K. Wilmann P.G. Dudek N.L. Purcell A.W. Revisiting the arthritogenic peptide theory: Quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes Arthritis Rheumatol. 2015 67 702 713 10.1002/art.38963 25418920 34. Colbert R.A. DeLay M.L. Layh-Schmitt G. Sowders D.P. HLA-B27 misfolding and spondyloarthropathies Adv. Exp. Med. Biol. 2009 649 217 234 19731632 35. Costello M.E. Ciccia F. Willner D. Warrington N. Robinson P.C. Gardiner B. Marshall M. Kenna T.J. Triolo G. Brown M.A. Brief Report: Intestinal dysbiosis in ankylosing spondylitis Arthritis Rheumatol. 2015 67 686 691 10.1002/art.38967 25417597 36. Breban M. Tap J. Leboime A. Said-Nahal R. Langella P. Chiocchia G. Furet J.P. Sokol H. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis Ann. Rheum. Dis. 2017 76 1614 1622 10.1136/annrheumdis-2016-211064 28606969 37. Breban M. Beaufrère M. Glatigny S. The microbiome in spondyloarthritis Best Pract. Res. Clin. Rheumatol. 2019 33 101495 10.1016/j.berh.2020.101495 32173258 38. Asquith M.J. Stauffer P. Davin S. Mitchell C. Lin P. Rosenbaum J.T. Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis Arthritis Rheumatol. 2016 68 2151 2162 10.1002/art.39681 26992013 39. Ciccia F. Bombardieri M. Principato A. Giardina A. Tripodo C. Porcasi R. Peralta S. Franco V. Giardina E. Craxi A. Overexpression of interleukin-23, but Not interleukin-17, as an immunologic signature of Subclinical intestinal inflammation in ankylosing spondylitis Arthritis Rheum. 2009 60 955 965 10.1002/art.24389 19333939 40. Cortes A. Pulit S.L. Leo P.J. Pointon J.J. Robinson P.C. Weisman M.H. Ward M. Gensler L.S. Zhou X. Garchon H.-J. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1 Nat. Commun. 2015 6 7146 10.1038/ncomms8146 25994336 41. Reveille J.D. Zhou X. Lee M.J. Weisman M.H. Yi L. Gensler L.S. Zou H. Ward M.M. Ishimori M.L. Learch T.J. HLA class i and II alleles in susceptibility to ankylosing spondylitis Ann. Rheum. Dis. 2019 78 66 73 10.1136/annrheumdis-2018-213779 30341055 42. Kim K. Bang S.Y. Lee S. Lee H.S. Shim S.C. Kang Y.M. Suh C.H. Sun C. Nath S.K. Bae S.C. An HLA-C amino-acid variant in addition to HLA-B*27 confers risk for ankylosing spondylitis in the Korean population Arthritis Res. Ther. 2015 17 342 10.1186/s13075-015-0855-3 26613595 43. Brown M.A. Jepson A. Young A. Whittle H.C. Greenwood B.M. Wordsworth B.P. Ankylosing spondylitis in West Africans—Evidence for a non-HLA-B27 protective effect Ann. Rheum. Dis. 1997 56 68 70 10.1136/ard.56.1.68 9059145 44. Reveille J.D. Witter J.P. Weisman M.H. Prevalence of axial spondylarthritis in the United States: Estimates from a cross-sectional Survey Arthritis Care Res. 2012 64 905 910 10.1002/acr.21621 45. Díaz-Peña R. Blanco-Gelaz M.A. Njobvu P. López-Vazquez A. Suárez-Álvarez B. López-Larrea C. Influence of HLA-B*5703 and HLA-B*1403 on susceptibility to spondyloarthropathies in the Zambian population J. Rheumatol. 2008 35 2236 2240 10.3899/jrheum.080395 18925686 46. Díaz-Peña R. Ouédraogo D.D. López-Vázquez A. Sawadogo S.A. López-Larrea C. Ankylosing spondylitis in three Sub-Saharan populations: HLA-B*27 and HLA-B*14 contribution Tissue Antigens 2012 80 14 15 10.1111/j.1399-0039.2012.01879.x 22536779 47. Benegas M. Muñoz-Gomariz E. Font P. Burgos-Vargas R. Chaves J. Palleiro D. Maldonado Cocco J. Gutiérrez M. Sáenz R. Steckmen I. Comparison of the clinical expression of patients with ankylosing spondylitis from Europe and Latin America J. Rheumatol. 2012 39 2315 2320 10.3899/jrheum.110687 23149388 48. Hsu K.C. Chida S. Geraghty D.E. Dupont B. The killer cell immunoglobulin-like receptor (KIR) genomic region: Gene-order, haplotypes and allelic polymorphism Immunol. Rev. 2002 190 40 52 10.1034/j.1600-065X.2002.19004.x 12493005 49. Cella M. Longo A. Ferrara G.B. Strominger J.L. Colonna M. NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80 J. Exp. Med. 1994 180 1235 1242 10.1084/jem.180.4.1235 7931060 50. Colonna M. Samaridis J. Cella M. Allen R.L. Callaghan C.A.O. Dunbar R. Ogg G.S. Cerundolo V. Rolink A. Angman L. Cutting Edge: Human Myelomonocytic Cells Express an Inhibitory Receptor for Classical and Nonclassical MHC Class I Molecules J. Immunol. 1998 160 3096 3100 9531263 51. Kollnberger S. Bird L. Sun M.Y. Retiere C. Braud V.M. McMichael A. Bowness P. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers Arthritis Rheum. 2002 46 2972 2982 10.1002/art.10605 12428240 52. Wong-Baeza I. Ridley A. Shaw J. Hatano H. Rysnik O. McHugh K. Piper C. Brackenbridge S. Fernandes R. Chan A. KIR3DL2 Binds to HLA-B27 Dimers and Free H Chains More Strongly than Other HLA Class I and Promotes the Expansion of T Cells in Ankylosing Spondylitis J. Immunol. 2013 190 3216 3224 10.4049/jimmunol.1202926 23440420 53. Martin M.P. Nelson G. Lee J.-H. Pellett F. Gao X. Wade J. Wilson M.J. Trowsdale J. Gladman D. Carrington M. Cutting Edge: Susceptibility to Psoriatic Arthritis: Influence of Activating Killer Ig-Like Receptor Genes in the Absence of Specific HLA-C Alleles J. Immunol. 2002 169 2818 2822 10.4049/jimmunol.169.6.2818 12218090 54. Williams F. Meenagh A. Sleator C. Cook D. Fernandez-Vina M. Bowcock A.M. Middleton D. Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis Hum. Immunol. 2005 66 836 841 10.1016/j.humimm.2005.04.005 16112031 55. Holm S.J. Sakuraba K. Mallbris L. Wolk K. Ståhle M. Sánchez F.O. Distinct HLA-C/KIR genotype profile associates with guttate psoriasis J. Investig. Dermatol. 2005 125 721 730 10.1111/j.0022-202X.2005.23879.x 16185272 56. Lopez-Larrea C. Blanco-Gelaz M.A. Torre-Alonso J.C. Armas J.B. Suarez-Alvarez B. Pruneda L. Couto A.R. Gonzalez S. Lopez-Vázquez A. Martinez-Borra J. Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations Arthritis Res. Ther. 2006 8 R101 10.1186/ar1988 16805919 57. Díaz-Peña R. Blanco-Gelaz M.A. Suárez-Álvarez B. Martínez-Borra J. López-Vázquez A. Alonso-Arias R. Brüges-Armas J. Vidal-Castiñeira J.R. López-Larrea C. Activating KIR genes are associated with ankylosing spondylitis in Asian populations Hum. Immunol. 2008 69 437 442 10.1016/j.humimm.2008.04.012 18638658 58. Harvey D. Pointon J.J. Sleator C. Meenagh A. Farrar C. Sun J.Y. Senitzer D. Middleton D. Brown M.A. Wordsworth B.P. Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis Ann. Rheum. Dis. 2009 68 595 598 10.1136/ard.2008.095927 19019897 59. Zvyagin I.V. Mamedov I.Z. Britanova O.V. Staroverov D.B. Nasonov E.L. Bochkova A.G. Chkalina A.V. Kotlobay A.A. Korostin D.O. Rebrikov D.V. Contribution of functional KIR3DL1 to ankylosing spondylitis Cell. Mol. Immunol. 2010 7 471 476 10.1038/cmi.2010.42 20818412 60. Jiao Y.L. Zhang B.C. You L. Li J.F. Zhang J. Ma C.Y. Cui B. Wang L.C. Chen Z.J. Zhao Y.R. Polymorphisms of KIR gene and HLA-C alleles: Possible association with susceptibility to HLA-B27-positive patients with ankylosing spondylitis J. Clin. Immunol. 2010 30 840 844 10.1007/s10875-010-9444-z 20652381 61. Díaz-Peña R. Vidal-Castiñeira J.R. Alonso-Arias R. Suarez-Alvarez B. Vicario J.L. Solana R. Collantes E. López-Vázquez A. Martínez-Borra J. López-Larrea C. Association of the KIR3DS1*013 and KIR3DL1*004 alleles with susceptibility to ankylosing Spondylitis Arthritis Rheum. 2010 62 1000 1006 10.1002/art.27332 20131260 62. Tajik N. Shahsavar F. Poormoghim H. Radjabzadeh M.F. Mousavi T. Jalali A. KIR3DL1+HLA-B Bw4 Ile80 and KIR2DS1+HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population Int. J. Immunogenet. 2011 38 403 409 10.1111/j.1744-313X.2011.01024.x 21797986 63. Wang S. Li G. Ge R. Duan Z. Zeng Z. Zhang T. Gao J. Yang T. Liu S. Wu S. Association of KIR genotype with susceptibility to HLA-B27-positive ankylosing spondylitis Mod. Rheumatol. 2013 23 538 541 10.3109/s10165-012-0692-z 22744805 64. Moon S.J. Oh E.J. Kim Y. Kim K.S. Kwok S.K. Ju J.H. Park K.S. Kim H.Y. Park S.H. Diversity of killer cell immunoglobulin-like receptor genes in uveitis associated with autoimmune diseases: Ankylosing spondylitis and behçet disease Ocul. Immunol. Inflamm. 2013 21 135 143 10.3109/09273948.2012.754905 23697859 65. Chandran V. Bull S.B. Pellett F.J. Ayearst R. Pollock R.A. Gladman D.D. Killer-cell immunoglobulin-like receptor gene polymorphisms and susceptibility to psoriatic arthritis Rheumatology 2014 53 233 239 10.1093/rheumatology/ket296 24185760 66. Díaz-Peña R. Vidal-Castiñeira J.R. Mulero J. Sánchez A. Queiro R. López-Larrea C. Activating killer immunoglobulin-like receptors genes are associated with increased susceptibility to ankylosing spondylitis Clin. Exp. Immunol. 2015 180 201 206 10.1111/cei.12568 25491925 67. Mahmoudi M. Jamshidi A.R. Karami J. Mohseni A. Amirzargar A.A. Farhadi E. Ahmadzadeh N. Nicknam M.H. Analysis of killer cell immunoglobulin-like receptor genes and their HLA ligands in Iranian patients with Ankylosing Spondylitis Iran. J. Allergy Asthma Immunol. 2016 15 27 38 26996109 68. Berinstein J. Pollock R. Pellett F. Thavaneswaran A. Chandran V. Gladman D.D. Association of variably expressed KIR3dl1 alleles with psoriatic disease Clin. Rheumatol. 2017 36 2261 2266 10.1007/s10067-017-3784-5 28801811 69. Wang C.M. Wang S.H. Wu Y.J. Lin J.C. Wu J. Chen J.Y. Human leukocyte antigen c*12:02:02 and killer immunoglobulin-like receptor 2dl5 are distinctly associated with ankylosing spondylitis in the Taiwanese Int. J. Mol. Sci. 2017 18 1775 10.3390/ijms18081775 70. Sun H.S. Liu D.X. Bai Y.Y. Hu N.W. Disease-association of different killer cell immunoglobulin-like receptors (KIR) and HLA-C gene combinations in reactive arthritis Mod. Rheumatol. 2019 29 531 537 10.1080/14397595.2018.1483292 29848119 71. Enciso-Vargas M. Alvarado-Ruíz L. Suárez-Villanueva A.S. Macías-Barragán J. Montoya-Buelna M. Oceguera-Contreras E. Alvarado-Navarro A. Graciano-Machuca O. Association Study between Psoriatic Arthritis and Killer Immunoglobulin-Like Receptor (KIR) Genes: A Meta-Analysis Immunol. Investig. 2020 1 12 10.1080/08820139.2020.1713145 72. Díaz-Peña R. Aransay A.M. Bruges-Armas J. López-Vázquez A. Rodríguez-Ezpeleta N. Mendibil I. Sánchez A. Torre-Alonso J.C. Bettencourt B.F. Mulero J. Fine mapping of a major histocompatibility complex in ankylosing spondylitis: Association of the HLA-DPA1 and HLA-DPB1 regions Arthritis Rheum. 2011 63 3305 3312 10.1002/art.30555 21769851 73. Díaz-Peña R. Castro-Santos P. Aransay A.M. Brüges-Armas J. Pimentel-Santos F.M. López-Larrea C. Genetic study confirms association of HLA-DPA1*01:03 subtype with ankylosing spondylitis in HLA-B27-positive populations Hum. Immunol. 2013 74 764 767 10.1016/j.humimm.2013.02.001 23459078 74. Tam V. Patel N. Turcotte M. Bossé Y. Paré G. Meyre D. Benefits and limitations of genome-wide association studies Nat. Rev. Genet. 2019 20 467 484 10.1038/s41576-019-0127-1 31068683 75. Burton P.R. Clayton D.G. Cardon L.R. Craddock N. Deloukas P. Duncanson A. Kwiatkowski D.P. McCarthy M.I. Ouwehand W.H. Samani N.J. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants Nat. Genet. 2007 39 1329 1337 17952073 76. Costantino F. Breban M. Garchon H.J. Genetics and Functional Genomics of Spondyloarthritis Front. Immunol. 2018 9 2933 10.3389/fimmu.2018.02933 30619293 77. Chang S.C. Momburg F. Bhutani N. Goldberg A.L. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism Proc. Natl. Acad. Sci. USA 2005 102 17107 17112 10.1073/pnas.0500721102 16286653 78. Martín-Esteban A. Sanz-Bravo A. Guasp P. Barnea E. Admon A. López de Castro J.A. Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome J. Autoimmun. 2017 79 28 38 10.1016/j.jaut.2016.12.008 28063628 79. Hanson A.L. Cuddihy T. Haynes K. Loo D. Morton C.J. Oppermann U. Leo P. Thomas G.P. Lê Cao K.A. Kenna T.J. Genetic Variants in ERAP1 and ERAP2 Associated With Immune-Mediated Diseases Influence Protein Expression and the Isoform Profile Arthritis Rheumatol. 2018 70 255 265 10.1002/art.40369 29108111 80. Maben Z. Arya R. Rane D. An W.F. Metkar S. Hickey M. Bender S. Ali A. Nguyen T.T. Evnouchidou I. Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1 J. Med. Chem. 2020 63 103 121 10.1021/acs.jmedchem.9b00293 31841350 81. Duerr R.H. Taylor K.D. Brant S.R. Rioux J.D. Silverberg M.S. Daly M.J. Steinhart A.H. Abraham C. Regueiro M. Griffiths A. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene Science 2006 314 1461 1463 10.1126/science.1135245 17068223 82. Cargill M. Schrodi S.J. Chang M. Garcia V.E. Brandon R. Callis K.P. Matsunami N. Ardlie K.G. Civello D. Catanese J.J. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes Am. J. Hum. Genet. 2007 80 273 290 10.1086/511051 17236132 83. Baeten D. Baraliakos X. Braun J. Sieper J. Emery P. Van Der Heijde D. McInnes I. Van Laar J.M. Landewé R. Wordsworth P. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: A randomised, double-blind, placebo-controlled trial Lancet 2013 382 1705 1713 10.1016/S0140-6736(13)61134-4 24035250 84. Vecellio M. Roberts A.R. Cohen C.J. Cortes A. Knight J.C. Bowness P. Wordsworth B.P. The genetic association of RUNX3 with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression Ann. Rheum. Dis. 2016 75 1534 1540 10.1136/annrheumdis-2015-207490 26452539 85. Apel M. Uebe S. Bowes J. Giardina E. Korendowych E. Juneblad K. Pasutto F. Ekici A.B. McManus R. Ho P. Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground with Ankylosing Spondylitis Arthritis Rheum. 2013 65 1224 1231 10.1002/art.37885 23401011 86. Cruz-Guilloty F. Pipkin M.E. Djuretic I.M. Levanon D. Lotem J. Lichtenheld M.G. Groner Y. Rao A. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs J. Exp. Med. 2009 206 51 59 10.1084/jem.20081242 19139168 87. Lotem J. Levanon D. Negreanu V. Bauer O. Hantisteanu S. Dicken J. Groner Y. Runx3 at the interface of immunity, inflammation and cancer Biochim. Biophys. Acta-Rev. Cancer 2015 1855 131 143 10.1016/j.bbcan.2015.01.004 88. Reveille J.D. Sims A.M. Danoy P. Evans D.M. Leo P. Pointon J.J. Jin R. Zhou X. Bradbury L.A. Appleton L.H. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci Nat. Genet. 2010 42 123 127 20062062 89. Evans D.M. Spencer C.C. Pointon J.J. Su Z. Harvey D. Kochan G. Oppermann U. Dilthey A. Pirinen M. Stone M. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility Nat. Genet. 2011 43 761 767 10.1038/ng.873 21743469 90. Liu Y. Helms C. Liao W. Zaba L.C. Duan S. Gardner J. Wise C. Miner A. Malloy M.J. Pullinger C.R. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci PLoS Genet. 2008 4 e1000041 10.1371/journal.pgen.1000041 18369459 91. Hüffmeier U. Uebe S. Ekici A.B. Bowes J. Giardina E. Korendowych E. Juneblad K. Apel M. McManus R. Ho P. Common variants at TRAF3IP2 are asociated with susceptibility to psoriatic arthritis and psoriasis Nat. Genet. 2010 42 996 999 10.1038/ng.688 20953186 92. Ellinghaus E. Stuart P.E. Ellinghaus D. Nair R.P. Debrus S. Raelson J.V. Belouchi M. Tejasvi T. Li Y. Tsoi L.C. Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL J. Investig. Dermatol. 2012 132 1133 1140 10.1038/jid.2011.415 22170493 93. Chen J. Yuan F. Fan X. Wang Y. Psoriatic arthritis: A systematic review of non-HLA genetic studies and important signaling pathways Int. J. Rheum. Dis. 2020 online 10.1111/1756-185X.13879 32761870 94. Bergström A. McCarthy S.A. Hui R. Almarri M.A. Ayub Q. Danecek P. Chen Y. Felkel S. Hallast P. Kamm J. Insights into human genetic variation and population history from 929 diverse genomes Science 2020 367 eaay5012 10.1126/science.aay5012 32193295 95. Mills M.C. Rahal C. The GWAS Diversity Monitor tracks diversity by disease in real time Nat. Genet. 2020 52 242 243 10.1038/s41588-020-0580-y 32139905 96. Manolio 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. Finding the missing heritability of complex diseases Nature 2009 461 747 753 10.1038/nature08494 19812666 97. Génin E. Missing heritability of complex diseases: Case solved? Hum. Genet. 2020 139 103 113 10.1007/s00439-019-02034-4 31165258 98. Robinson P.C. Leo P.J. Pointon J.J. Harris J. Cremin K. Bradbury L.A. Stebbings S. Harrison A.A. Duncan E.L. Evans D.M. Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease NPJ Genom. Med. 2016 1 16008 10.1038/npjgenmed.2016.8 29263810 99. O’Rielly D.D. Uddin M. Codner D. Hayley M. Zhou J. Pena-Castillo L. Mostafa A.A. Hasan S.M.M. Liu W. Haroon N. Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis Ann. Rheum. Dis. 2016 75 772 779 10.1136/annrheumdis-2014-206484 25956157 100. Rong J. Li Q. Zhang P. Wu X. Huang J. Li C. Liao Z. Xie Y. Lv Q. Wei Q. A rare co-segregation-mutation in the insulin receptor substrate 1 gene in one Chinese family with ankylosing spondylitis PLoS ONE 2015 10 e0126348 10.1371/journal.pone.0126348 25978640 101. Tan Z. Zeng H. Xu Z. Tian Q. Gao X. Zhou C. Zheng Y. Wang J. Ling G. Wang B. Identification of ANKDD1B variants in an ankylosing spondylitis pedigree and a sporadic patient BMC Med. Genet. 2018 19 111 10.1186/s12881-018-0622-9 29976160 102. Feng Y. Hong Y. Zhang X. Cao C. Yang X. Lai S. Fan C. Cheng F. Yan M. Li C. Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis Gene 2018 668 121 128 10.1016/j.gene.2018.05.057 29778423 103. Conrad D.F. Pinto D. Redon R. Feuk L. Gokcumen O. Zhang Y. Aerts J. Andrews T.D. Barnes C. Campbell P. Origins and functional impact of copy number variation in the human genome Nature 2010 464 704 712 10.1038/nature08516 19812545 104. Uddin M. Maksymowych W.P. Inman R. Gladman D. Munn A. Yazdani R. Pellett F. Hamilton S. O’Rielly D.D. Rahman P. UGT2B17 copy number gain in a large ankylosing spondylitis multiplex family BMC Genet. 2013 14 67 10.1186/1471-2156-14-67 23927372 105. Jung S.H. Yim S.H. Hu H.J. Lee K.H. Lee J.H. Sheen D.H. Lim M.K. Kim S.Y. Park S.W. Kim S.H. Genome-wide copy number variation analysis identifies deletion variants associated with ankylosing spondylitis Arthritis Rheumatol. 2014 66 2103 2112 10.1002/art.38650 24692264 106. Wei W.H. Hemani G. Haley C.S. Detecting epistasis in human complex traits Nat. Rev. Genet. 2014 15 722 733 10.1038/nrg3747 25200660 107. Kirino Y. Bertsias G. Ishigatsubo Y. Mizuki N. Tugal-Tutkun I. Seyahi E. Ozyazgan Y. Sacli F.S. Erer B. Inoko H. Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1 Nat. Genet. 2013 45 202 207 10.1038/ng.2520 23291587 108. Genetic Analysis of Psoriasis Consortium The Wellcome Trust Case Control Consortium 2 Strange A. Capon F. Spencer C.C. Knight J. Weale M.E. Allen M.H. Barton A. Band G. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1 Nat. Genet. 2010 42 985 990 20953190 109. Castro-Santos P. Moro-García M.A. Marcos-Fernández R. Alonso-Arias R. Díaz-Peña R. ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population Innate Immun. 2017 23 476 481 10.1177/1753425917716527 28651467 110. Caulfield T. Fullerton S.M. Ali-Khan S.E. Arbour L. Burchard E.G. Cooper R.S. Hardy B.J. Harry S. Hyde-Lay R. Kahn J. Race and ancestry in biomedical research: Exploring the challenges Genome Med. 2009 1 1 8 10.1186/gm8 19348688 111. Yang J. Benyamin B. McEvoy B.P. Gordon S. Henders A.K. Nyholt D.R. Madden P.A. Heath A.C. Martin N.G. Montgomery G.W. Common SNPs explain a large proportion of the heritability for human height Nat. Genet. 2010 42 565 569 10.1038/ng.608 20562875 112. Loh P.R. Bhatia G. Gusev A. Finucane H.K. Bulik-Sullivan B.K. Pollack S.J. De Candia T.R. Lee S.H. Wray N.R. Kendler K.S. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis Nat. Genet. 2015 47 1385 1392 10.1038/ng.3431 26523775 113. Jansen P.R. Watanabe K. Stringer S. Skene N. Bryois J. Hammerschlag A.R. de Leeuw C.A. Benjamins J.S. Muñoz-Manchado A.B. Nagel M. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways Nat. Genet. 2019 51 394 403 10.1038/s41588-018-0333-3 30804565 114. Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. Analysis of protein-coding genetic variation in 60,706 humans Nature 2016 536 285 291 10.1038/nature19057 27535533 115. Brown M.A. Li Z. Cao K.A.L. Biomarker development for axial spondyloarthritis Nat. Rev. Rheumatol. 2020 16 448 463 10.1038/s41584-020-0450-0 32606474 116. Torkamani A. Wineinger N.E. Topol E.J. The personal and clinical utility of polygenic risk scores Nat. Rev. Genet. 2018 19 581 590 10.1038/s41576-018-0018-x 29789686 117. Khera A.V. Chaffin M. Aragam K.G. Haas M.E. Roselli C. Choi S.H. Natarajan P. Lander E.S. Lubitz S.A. Ellinor P.T. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations Nat. Genet. 2018 50 1219 1224 10.1038/s41588-018-0183-z 30104762 118. Rostami S. Hoff M. Brown M.A. Hveem K. Holmen O.L. Fritsche L.G. Videm V. Prediction of ankylosing spondylitis in the HUNT study by a genetic risk score combining 110 single-nucleotide polymorphisms of genome-wide significance J. Rheumatol. 2020 47 204 210 10.3899/jrheum.181209 30936278 119. Knevel R. Cessie S.L. Terao C.C. Slowikowski K. Cui J. Huizinga T.W.J. Costenbader K.H. Liao K.P. Karlson E.W. Raychaudhuri S. Using genetics to prioritize diagnoses for rheumatology outpatients with inflammatory arthritis Sci. Transl. Med. 2020 12 eaay1548 10.1126/scitranslmed.aay1548 32461333 120. Martin A.R. Kanai M. Kamatani Y. Okada Y. Neale B.M. Daly M.J. Clinical use of current polygenic risk scores may exacerbate health disparities Nat. Genet. 2019 51 584 591 10.1038/s41588-019-0379-x 30926966