Identification of new susceptibility loci associated with rheumatoid arthritis

2020 ◽  
Vol 79 (12) ◽  
pp. 1565-1571
Author(s):  
Rui-Xue Leng ◽  
Dong-Sheng Di ◽  
Jing Ni ◽  
Xiao-Xiao Wu ◽  
Lin-Lin Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Luciferase Reporter ◽  
Study Cohort ◽  
Susceptibility Loci ◽  
Cytokine Assay

ObjectivesThe present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).MethodsWe performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function.ResultsWe identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta <5.00E−08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and genes within four loci are known functional players in autoimmunity, which supports the validity of our findings. The reporter assay showed that the risk allele of rs8030390 in IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets.ConclusionThis study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.

scholarly journals Association of the RPA3-UMAD1 locus with interstitial lung diseases complicated with rheumatoid arthritis in Japanese

2020 ◽  
Vol 79 (10) ◽  
pp. 1305-1309
Author(s):  
Yuya Shirai ◽  
Suguru Honda ◽  
Katsunori Ikari ◽  
Masahiro Kanai ◽  
Yoshito Takeda ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Meta Analysis ◽  
Interstitial Lung Diseases ◽  
Ct Image ◽  
Significance Threshold ◽  
Genome Wide ◽  
Stratified Analysis ◽  
Image Pattern

ObjectivesThe genetic background of rheumatoid arthritis–interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans.MethodsWe performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern.ResultsWe identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at RPA3-UMAD1, OR=2.04, 95% CI 1.59 to 2.60, p=1.5×10−8). Subsequent stratified analysis based on the CT image patterns demonstrated that the effect size of the RA-ILD risk allele (rs12702634-C) was large with the UIP pattern (OR=1.86, 95% CI 0.97 to 3.58, p=0.062) and the probable UIP pattern (OR=2.26, 95% CI 1.36 to 3.73, p=0.0015).ConclusionWe revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at RPA3-UMAD1 was relatively high in the CT image patterns related to fibrosis. Our study should contribute to elucidation of the complicated aetiology of RA-ILD.

scholarly journals Using a Two-Sample Mendelian Randomization Method in Assessing the Causal Relationships Between Human Blood Metabolites and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Zixian Wang ◽  
Shiyu Chen ◽  
Qian Zhu ◽  
Yonglin Wu ◽  
Guifeng Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Blood ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Blood Metabolites ◽  
Causal Relationships

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P &lt; 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.

scholarly journals Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes

2019 ◽  
Vol 4 ◽  
pp. 113 ◽  
Author(s):  
Venexia M Walker ◽  
Neil M Davies ◽  
Gibran Hemani ◽  
Jie Zheng ◽  
Philip C Haycock ◽  
...  
Keyword(s):  
Risk Factors ◽  
Web Application ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
R Package ◽  
Sensitivity Analyses ◽  
Link Type ◽  
Study Results

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.

scholarly journals Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Masahiro Miyake ◽  
Rosa L. Schellevis ◽  
Camiel J. F. Boon ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Central Serous Chorioretinopathy ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Association Analyses ◽  
Age Related ◽  
Genome Wide

AbstractThe recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.

scholarly journals Body Mass Index and the Risk of Rheumatoid Arthritis: An Updated Dose-Response Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Xia Feng ◽  
Xizhu Xu ◽  
Yanjun Shi ◽  
Xuezhen Liu ◽  
Huamin Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Body Mass Index ◽  
Body Mass ◽  
Dose Response ◽  
Meta Analysis ◽  
Prevention Strategy ◽  
Sensitivity Analyses ◽  
Significant Heterogeneity ◽  
Nonlinear Relationship ◽  
Increased Risk

Background. Extensive studies have been carried out to investigate the association between obesity and the risk of rheumatoid arthritis (RA); however, the results of the current reported original studies remain inconsistent. This study aimed to clarify the relationship between body mass index and rheumatoid arthritis by conducting an updated overall and dose-response meta-analysis. Methods. The relevant literature was searched using the PubMed and Embase databases (through 20 September 2018) to identify all eligible published studies. Random-effect models and dose-response meta-analyses were used to estimate the pooled risk ratio (RR) with a 95% confidence interval (CI). Subgroup analyses were also conducted based on the characteristics of the participants. Sensitivity analyses and publication bias tests were also performed to explore potential heterogeneity and bias in the meta-analysis. Results. Sixteen studies that included a total of 406,584 participants were included in the meta-analysis. Compared to participants with normal weight, the pooled RRs of rheumatoid arthritis were 1.12 (95% CI, 1.04-1.20) in overweight and 1.23 (95% CI, 1.09-1.39) in obese participants. There was evidence of a nonlinear relationship between body mass index (BMI) and RA (P  for nonlinearity less than 0.001 in the overall meta-analysis, P for nonlinearity=0.025 in the case-control studies, P for nonlinearity=0.0029 in the cohort studies). No significant heterogeneity was found among studies (I2=10.9% for overweight and I2=45.5% for obesity). Conclusion. The overall and dose-response meta-analysis showed that increased BMI was associated with an increased risk for rheumatoid arthritis, which might present a prevention strategy for the prevention or control of rheumatoid arthritis. The nonlinear relationship between BMI and RA might present a personal prevention strategy for RA.

scholarly journals Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci

2020 ◽  
pp. annrheumdis-2020-219065
Author(s):  
Eunji Ha ◽  
Sang-Cheol Bae ◽  
Kwangwoo Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
T Cell Activation ◽  
Fixed Effects ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Chromatin Interaction ◽  
Susceptibility Loci ◽  
European Populations

ObjectivesNearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations.MethodsGenome-wide RA association summary statistics in three large case–control collections consisting of 311 292 individuals of Korean, Japanese and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritise causal variants and genes, RA variant-implicating features (tissues, pathways and transcription factors) and potentially repurposable drugs for RA treatment.ResultsWe identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the single-nucleotide polymorphism-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-human leukocyte antigens (HLA) susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription–activation histone marks that simultaneously highlighted the importance of CD4+ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications.ConclusionOur findings provide useful insights regarding RA genetic aetiology and variant-driven RA pathogenesis.

scholarly journals Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children

2019 ◽  
Vol 111 (12) ◽  
pp. 1350-1357 ◽  
Author(s):  
Maoxiang Qian ◽  
Xujie Zhao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Yoshihiro Gocho ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Luciferase Assay ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts. Methods We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided. Results A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias. Conclusions These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).

scholarly journals Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

2010 ◽  
Vol 42 (6) ◽  
pp. 508-514 ◽  
Author(s):  
Eli A Stahl ◽  
◽  
Soumya Raychaudhuri ◽  
Elaine F Remmers ◽  
Gang Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Rheumatoid Arthritis Risk ◽  
Genome Wide

scholarly journals A Further Comment on ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ by Lam et al.

2018 ◽  
Vol 21 (6) ◽  
pp. 538-545 ◽  
Author(s):  
W. D. Hill
Keyword(s):  
Cognitive Ability ◽  
Drug Targets ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Tissue Specific ◽  
Nootropic Drug ◽  
Genome Wide ◽  
Quality Control Metrics

Lam et al. (2018) respond to a commentary of their paper entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ Lam et al. (2017). While Lam et al. (2018) have now provided the recommended quality control metrics for their paper, problems remain. Specifically, Lam et al. (2018) do not dispute that the results of their multi-trait analysis of genome-wide association study (MTAG) analysis has produced a phenotype with a genetic correlation of one with three measures of education, but do claim the associations found are specific to the trait of cognitive ability. In this brief paper, it is empirically demonstrated that the phenotype derived by Lam et al. (2017) is more genetically similar to education than cognitive ability. In addition, it is shown that of the genome-wide significant loci identified by Lam et al. (2017) are loci that are associated with education rather than with cognitive ability.

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