Sparse block signal detection and identification for shared cross-trait association analysis

genotyping with in excess of 500,000 SNPs can now be readily achieved to accurately tag the vast majority of the diversity in the genome (Steemers et al., 2006;Gunderson et al., 2005;Reich et al., 2005).GWAS has been enormously successful through large-scale studies of cohorts of patients and controls, providing compelling evidences for genetic variants involved in complex autoimmune diseases.A full catalog of these studies is now available at the NIH website: http://www.genome.gov/gwastudies(Hindorff et al., 2010).We are now in a rapid phase of data accumulation for many complex disorders, especially T1D and IBD.57 loci have now been uncovered to date as being robustly associated with pathogenesis of T1D.The chronic IBDs have seen a great success as well.To date there are 99 IBD susceptibility loci: 71 associated with CD, 47 with UC, and 28 with both UC and CD.In this review, we first provide a summary of these recent discoveries and then discuss the shared susceptibility loci implicated in T1D, UC and CD.Our study helps understanding the genetic architecture, including shared genetic pathways and risk factors with opposing effects for these related diseases.Data were obtained from two main sources: the National Human Genome Research Institute catalogue of published genome-wide association studies (http://www.genome.gov/gwastudies/;last accessed on 1 April 2011); and PubMed literature search. Type 1 diabetes (T1D)T1D results from autoimmune destruction of pancreatic beta cells, resulting in a lack of insulin production.Of all cases of diabetes, T1D represents approximately 10% and is most prevalent in populations of European ancestry, where there is ample evidence of increased annual incidence during the past five decades (Onkamo et al., 1999; EURODIAB ACE Study Group, 2000).T1D risk is strongly influenced by multiple genetic loci and poorly understood environmental factors. A genetic component to type 1 diabetesT1D is a complex trait that results from the interplay between environmental and genetic factors.Many evidences support a strong genetic component associated to T1D.The epidemiological data for geographic prevalence differences is one clear indicator, with populations of European ancestry having the highest presentation rate.T1D has high concordance among monozygotic twins (33 to 42%) (Redondo et al., 2001) and runs strongly in families, with the sibling risk being approximately 10 times greater than the general population (Clayton, 2009); this is in clear contrast to the "less genetic" type 2 diabetes (T2D), where the sibling risk ratio is relatively modest at 3.5 (Rich, 1990). Before GWASHistorically, prior to GWAS, only five loci have been fully established to be associated with T1D.It has been long established that approximately half of the genetic risk for T1D is conferred by the genomic region harboring the HLA class II genes (primarily HLA-DRB1, -DQA1 and -DQB1 genes), which encode the highly polymorphic antigen-presenting proteins.Recent fine mapping efforts of the MHC addressed why the class II genes HLA-DQB1 and HLA-DRB1 cannot completely explain the association between T1D and the MHC region (Nejentsev et al., 2007).It turned out that most of the remaining association that could be detected was due to signals in HLA-B and HLA-A, and that the existence of other major T1D genes in the extended MHC was unlikely.Other established loci prior to www.intechopen.com

Systemic lupus erythematosus (SLE) is characterized as an autoimmune disorder with unclear etiology. \n\nTo identify the genetic effect of SLE, a genome wide association study (GWAS) and its further replication were conducted on SLE patients in Asian populations and ethnically matched controls. Before this study, most of the confirmed association loci were identified by GWAS studies in European populations. Apart from the established associations, we identified a SLE susceptible single nucleotide polymorphisms (SNP) located in ETS1 (rs1128334, P=2.3E-11, OR=1.29) in four different cohorts. This locus is probably an Asian-specific susceptibility locus since no Caucasian study has reported further validation in the last years. A new susceptibility variant in UHRF1BP1 (rs13205210, P=4.4E-09, OR=1.49) independent from the previously confirmed SNPs in Caucasian study was also confirmed to be associated with SLE in the Hong Kong Chinese population.\n\n\n\nMeta-analysis was performed by introducing another Chinese Han GWAS data set from Anhui province, China. Three loci, TET3-DGUOK, CD80, DRAM1, were confirmed to be associated with SLE. Two loci with suggestive signals in Hong Kong GWAS and further replication were also confirmed by the meta-analysis: PTTG1-MiRNA146a, YDJC.\n\n\n\nIn order to identify the genetic effect for females who have predominant chance to suffer from SLE, X chromosome specific meta-analysis based on the Hong Kong and Anhui GWAS data and further replication study were performed by considering the difference between females and males. A signal in PRPS2, and three independent signals in the Xq28 were confirmed with the replication in three different cohorts by considering both females and males.\n\n\n\nGene-gene interactions were also investigated genome-widely in a hypothesis free manner based on the meta-analysis results. The further validation processes were preceeded based on each independent GWAS data set. Four pairswise interacting loci were found and cross validated by three methods including logistic regression and Multifactor Dimensionality Reduction (MDR) and information gain theory based on the Anhui GWAS data set. Further studies are still needed to better explain the real features of genetic epistasis and the potential biological roles.\n\n\n\nBy incorporating two GWAS from the same population, the population difference is efficiently avoided. Together with the putative gene-gene interactions, this study presents a comprehensive analysis based on the GWAS data conducted on SLE. It may shed new light on the disease mechanisms of SLE.

SNPpattern: A Genetic Tool to Derive Haplotype Blocks and Measure Genomic Diversity in Populations Using SNP Genotypes

Investigation of idiopathic inflammatory myopathy for shared genetic risk factors with other autoimmune diseases: results from the European Myositis Network

CVID is the most common clinically encountered primary antibody deficiency disorder and can be associated with autoimmune complications. We report 2 children with CVID who developed joint symptoms several years after initial diagnosis and were referred to a pediatric rheumatologist, who suspected temporomandibular joint arthritis clinically. Both patients underwent MRI imaging with contrast administration, which confirmed temporomandibular arthritis. They were successfully treated with intra-articular steroid joint injections. Juvenile idiopathic arthritis (JIA) can be one of the autoimmune associations with CVID, but temporomandibular arthritis as the primary manifestation is uncommon, difficult to detect clinically and has not been described previously in CVID. Although jaw pain and discomfort on chewing might indicate underlying temporomandibular joint arthritis, these symptoms might not necessarily be present. If not promptly identified and treated, arthritis of JIA can cause joint damage/disability and therefore needs specialist multidisciplinary management under a pediatric rheumatologist. JIA may not respond to steroid injections alone and might require escalation in therapy with systemic immunosuppressive agents. Little is known about the intricacies of systemic immunosuppressive therapy in patients with CVID who develop JIA. Conclusion:In relation to CVID, juvenile idiopathic arthritis (JIA) can be an associated autoimmune manifestation. JIA presenting as temporomandibular joint arthritis as the first manifestation is unusual but can occur and might be potentially difficult to detect clinically. Pediatricians should be aware of the possibility of JIA in a child with CVID and refer to a pediatric rheumatologist for appropriate management. If not treated promptly, JIA can cause joint destruction and disability.

Despite the development of genomic research on common cardiovascular diseases, genetic variants and/or loci shown to be disease associated have been seldom applied to risk prediction in a clinical setting, although they could provide us with novel mechanistic insights into the pathophysiology and potential therapeutic targets. Here, we discuss the significance and limitations of the up-to-date genomic studies on common diseases and propose what kind of genomic research should be prioritized in view of the realization of precision medicine. Many disease-associated loci have been identified using a genome-wide association study (GWAS) in a large-scale case–control design (more than several thousand cases and controls). A GWAS is an analytical method for the identification of disease-associated tag (lead) SNPs, which are indicators of disease-associated loci (linkage disequilibrium blocks) with a genome-wide significance ( P <5×10−8). Consequently, further analysis is required to identify the specific variants functioning as the most associated and/or risk variants1 within each disease-associated locus. Consistent with the genetic cause of monogenic diseases, novel biology on the risk genes and their regulatory pathways can be learned through detailed genetic and functional analysis after GWAS. Also, GWAS data on disease-associated pathways might be used in choosing drugs for treatment.2 We have experienced several successful stories. Single-nucleotide polymorphisms (SNPs) in PCSK9 , HMGCR , and NPC1L 1 were shown to be associated with hypercholesterolemia in GWAS on blood lipids.3 Although their effects shown in that GWAS were relatively weak (+2–3 mg/dL change in plasma cholesterol values), potent compounds targeting these gene-encoded proteins have been established as lipid-lowering agents (anti-PCSK9 antibody, statin, and ezetimibe, respectively). In this way, GWAS data can provide the scientific community with information about novel biology, mechanical pathways, and potential pharmaceutical drugs. Because current GWASs are usually performed with a case–control design, the results are …

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

All modern pepper accessions are products of the domestication of wild Capsicum species. However, due to the limited availability of genome-wide association study (GWAS) data and selection signatures for various traits, domestication-related genes have not been identified in pepper. Here, to address this problem, we obtained data for major fruit-related domestication traits (fruit length, width, weight, pericarp thickness, and fruit position) using a highly diverse panel of 351 pepper accessions representing the worldwide Capsicum germplasm. Using a genotype-by-sequencing (GBS) method, we developed 187,966 genome-wide high-quality SNP markers across 230 C. annuum accessions. Linkage disequilibrium (LD) analysis revealed that the average length of the LD blocks was 149 kb. Using GWAS, we identified 111 genes that were linked to 64 significant LD blocks. We cross-validated the GWAS results using 17 fruit-related QTLs and identified 16 causal genes thought to be associated with fruit morphology-related domestication traits, with molecular functions such as cell division and expansion. The significant LD blocks and candidate genes identified in this study provide unique molecular footprints for deciphering the domestication history of Capsicum. Further functional validation of these candidate genes should accelerate the cloning of genes for major fruit-related traits in pepper.

Patients with juvenile idiopathic arthritis (JIA) may develop adult rheumatic diseases later in life, and prolonged or recurrent disease activity is often associated with substantial disability; therefore, it is important to identify patients with JIA at high risk of developing adult rheumatic diseases and provide specialized attention and preventive care to them. To elucidate the full extent of the genetic association of JIA with adult rheumatic diseases, to improve treatment strategies and patient outcomes for patients at high risk of developing long-term rheumatic diseases. In this genetic association study of 4 disease genome-wide association study (GWAS) cohorts from 2013 to 2024 (JIA, rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], and systemic sclerosis [SSc]), patients in the JIA cohort were recruited from the US, Australia, and Norway (with a UK cohort included in the meta-analyzed cohort), while patients in the other 3 cohorts were recruited from US and Western European countries. All analyses were conducted between September 2023 and April 2024. Genetic associations. Genetic correlations and shared genomic loci between JIA and adult rheumatic diseases. Genetic correlation analyses and cross-trait meta-analysis were conducted on the JIA cohort and the summary statistics of the GWASs from adult rheumatic diseases (RA, SLE, and SSc). Mendelian randomization analyses were also conducted. This study included 33 207 patients across the 4 cohorts, with 4550 patients in the meta-analyzed JIA cohort (JIA cohort: 1485 patients with arthritis onset before 16 years; 1017 female [68.5%]; 10 352 controls; UK cohort: 3305 patients with JIA; 9196 controls), 143 61 patients in the RA cohort, 5201 patients in the SLE cohort; and 9095 patients in the SSc cohort. After the GWAS result of the JIA cohort was meta-analyzed with the UK JIA cohort, there was a total of 4550 JIA cases and 18 446 controls. The analysis revealed a significant global correlation between JIA and adult rheumatic diseases, with 84 regions harboring signals associated with multiple diseases. Cross-trait analyses uncovered novel disease loci and 20 loci associated with JIA and adult diseases. Mendelian randomization analysis revealed the significant association of 11 proteins with rheumatic disorders. Both shared, organ-specific, and disease-specific critical cell types were highlighted. In this genetic association study, there was significant genetic overlap between JIA and adult rheumatic diseases. These findings may help to refine JIA classification, risk stratification, and therapeutic strategy of repurposing adult disease drugs for pediatric patients with similar mechanisms.

Background Primary immunodeficiency (PID), common variable immunodeficiency (CVID) are primary immunodeficiencies with disorder of the adaptive immune system, organ-specific pathology, as well as defects in the gut microbiome [1]. In patients with ulcerative colitis (UC) during relapse, similar changes. Methods The aim of the research is a comprehensive study of the structure of gut microbiota and mucosal protein profile (MPP) in patients with PID, CVID and UC in different phases of the disease course. The research included 19 patients with PID, 28 with CVID and 32 with UC (22 with relapse and 10 with persistent remission of the disease), control group - 20 healthy volunteers. Estimation of gut microbiota was performed by microbacteriological seeding faeces (MSF). Content of short-chain fatty acids (SCFA) in the feces as determined by gas-chromatography-mass spectrometry (GC-MS). Mucosal protein profile was based on isoelectric focusing techniques (SDS-PAGE, 2DGE). Mass spectrograms were obtained using MALDI-TOF-MS/MS (Bruker, USA). Molecular interaction and functional characteristics of proteins were studied using the STRING 10.0 databases. Results SCFA production showed a 6-, 9- and 11-fold decrease in propionic and butyric acids, mainly in patients with PID and UC: 0.2 + 0.1, 0.14 + 0.03 and 0.04 + 0.02, 0.08 + 0.02 mg/g, respectively (tab. 1). MSF showed a decrease in titers of E. coli, bifido- and lactobacilli on average 4.6 + 0.8 Lg. The conditionally pathogenic microbiota was represented by E. coli, hemolytic strains (n=34,104/g), Proteus spp. (n=48,105/g), Staphylococcus spp. (n=29,105–6/g), Candida alb. / glabrata (n=55,104–6/g) and Clostridium spp. (n = 38,104/g). Results of MPP (detection rate of 75% or more) of the colon mucosa in patients with PID and CVID were detected: 1, 2, 4 okkludin, kininogen 1, interleukin-1B, interleukin 8, B2-glycoprotein, heat shock protein 27, in patients with CVID - translational elongation factor, apolipoprotein C-III. In patients with UC - NF-kB, alipoprotein C-III, TNF-α, heat shock protein 27, interleukin-2 and 8 were presented. MPP patients with UC (stable remission phase): a-enolase, b-defensin-1, cathepsin D, prohibitin (tab. 2). Conclusion 1. In patients with PID, CVID and UC during relapse, markers of damage to the intestinal microbiome, a decrease in the production of SCFA and proteins characteristic of inflammation, apoptosis, proliferation, as well as proteins reflecting the activity of the autoimmune process, were identified. 2. During the period of drug remission in patients with UC, PID and CVID, specific components of altered MPP disappear, and a tendency towards restoration of the gut microbiota and SCFA production is recorded. References Jørgensen SF, Trøseid M, Kummen M, et al. Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation. Mucosal Immunol. 2016; 9:1455-1465.

BackgroundA higher prevalence of celiac disease (CD) has been reported in patients with juvenile idiopathic arthritis (JIA) compared to the general population. Factors related to the increased risk of co-occurrence and associated disease course have not been fully elucidated. Aims of this study were to determine the prevalence of CD in a large Southern Italian cohort of children with JIA, describe their clinical features and disease course and investigate risk factors associated with their co-occurrence.FindingsDemographic, clinical and laboratory data of all patients with JIA admitted to our Pediatric Rheumatology Unit from January 2001 to June 2019, who underwent CD screening, were retrospectively extracted from clinical charts and analyzed. Eight of 329 JIA patients were diagnosed with CD, resulting in a prevalence higher than the general Italian population (2.4% vs 0.93%, p < 0.05). Familiarity for autoimmunity was reported by 87.5% patients with JIA and CD compared to 45.8% of those without CD (p < 0.05). 87.5% patients with JIA and CD required both a conventional Disease Modifying Anti-Rheumatic Drug (DMARD) and a biological DMARD over time compared to 36.4% of those without CD (p < 0.05).ConclusionA higher CD prevalence was found in a large JIA cohort, supporting the need for CD screening in all JIA children, especially those with a family history of autoimmunity, found to be associated with the co-occurrence of the two diseases. This is clinically relevant since patients with CD and JIA more often required a step-up therapy, suggesting a more severe JIA clinical course.

IntroductionSystemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking.MethodsThrough meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry.ResultsAll reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE.ConclusionsAssociation with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0577-6) contains supplementary material, which is available to authorized users.

Mendelian randomization analysis reveals causal associations between autoimmune diseases and female infertility risk.

Previous genome-wide association studies (GWAS) have identified various risk variants for ulcerative colitis (UC), but there is a lack of evidence showing how these variants contribute to the development of UC. We employed an integrated pipeline to effectively translate genetic associations in order to identify pathogenic genes for UC.By combining GWAS data for UC with proteomic data from the human brain and plasma, we conducted a protein-wide association study (PWAS) and utilized protein-protein interaction (PPI) network analysis to screen for potential key proteins. Subsequently, causal analysis was performed to assess the potential causal relationships between these proteins and the risk of developing UC.Multiple genes associated with UC were identified in the human brain and plasma proteomes, including known genes such as TYK2 and STAT3, as well as newly discovered genes such as NARS2. PPI networks revealed strong interactions among proteins, including TYK2, STAT3, and IL23R. Causal analysis indicated that 11 risk genes, including FCGR2A, showed significant causal associations with UC, and were linked to key processes related to immune regulation and inflammatory responses, suggesting their potential roles in the pathogenesis of UC.This study integrated GWAS and PWAS data to identify risk genes associated with UC, providing new insights into the disease's pathogenesis and potential therapeutic targets.

Sarcopenia and immune-mediated inflammatory diseases: Evaluating causality and exploring therapeutic targets for sarcopenia through Mendelian randomization.