Aug 2026· Genes· Vol 17, pp. 1031· 0 citations· 45 references
TL;DR
This study identifies divergent causal effects of selected AIDs on FL risk and demonstrates localized pleiotropy at key loci, providing novel insights into shared immunogenetic mechanisms.
Abstract
Background/Objectives: Epidemiological studies link autoimmune diseases (AIDs) to follicular lymphoma (FL) risk, but their shared genetic architecture and causal mechanisms remain unclear. Methods: A two-sample Mendelian randomization (MR) analysis was employed to assess causal relationships between 15 AIDs and FL. Pleiotropic loci were identified through the Pleiotropy Analysis under Composite Null (PLACO). Bayesian colocalization analysis, functional mapping, and Multi-marker Analysis of GenoMic Annotation were applied to fine-map shared genetic variants and identify their target genes. Summary data-based MR was used with multitissue expression quantitative trait locus data to infer causal effects of gene expression. HyPrColoc analysis was applied to decipher shared genetic regulation of immune cell phenotypes. Results: MR revealed that rheumatoid arthritis increased FL risk (ORIVW = 1.55, nominal p = 7.16 × 10−5, FDR-corrected p = 1.07 × 10−3), whereas composite autoimmune disease reduced FL risk (ORIVW = 0.70, nominal p = 4.61 × 10−5, FDR-corrected p = 6.92 × 10−4). Hypothyroidism showed only a nominally suggestive protective trend (ORIVW = 0.88, nominal p = 0.015), which did not survive Benjamini–Hochberg multiple-testing correction (FDR-corrected p = 0.075). Fifty-five pleiotropic loci shared between FL and AIDs were identified, among which key loci such as 1p36.32, 6p21.32, 17p13.1, and 11q23.3 exhibited strong colocalization evidence. Core pleiotropic genes (e.g., TNFRSF14, MMEL1, CXCR5, and RNASET2) were prioritized, which implicated pathways related to MHC class II antigen presentation, interferon signaling, and T cell activation. HyPrColoc analysis demonstrated that these loci colocalized with the expression of immune receptors, including BAFF-R on B cells and HVEM (TNFRSF14) on naïve CD8+ T cells. Conclusions: Our study identifies divergent causal effects of selected AIDs on FL risk and demonstrates localized pleiotropy at key loci, providing novel insights into shared immunogenetic mechanisms.
Evidence is provided for a shared, albeit modest, and genetic basis between EMS and IBD that is likely mediated through immune regulation, hormonal signaling, and tissue repair that is likely mediated through immune regulation, hormonal signaling, and tissue repair.
Xinyue Cui, Jian-Hong Wang, Jingjing Chen et al.· BioMed Research Internationa...· 0 citations
BACKGROUND
Rheumatoid Arthritis (RA) is a common autoimmune disease with complex pathogenesis and high prevalence, severely affecting patients' quality of life. Multi-omics analysis has emerged as a powerful tool in RA research, providing insights into cell heterogeneity, genetic mechanisms, and immune microenvironment characteristics. This research looks into important genes linked to rheumatoid arthritis(RA) using single-cell data and Mendelian randomization analysis, while also uncovering the characteristics of the immune microenvironment and its mechanisms linking to these key genes.
METHODS
Gene expression, eQTL, and GWAS data were collected. Analyses included single-cell data processing (quality control, dimensionality reduction, clustering, cell annotation, and cell subset contribution assessment), subgroup non-negative matrix factorization, Mendelian randomization, co-localization analysis, immune infiltration analysis, and GSEA/GSVA.
RESULTS
This study analyzed 95,036 single-cell samples and found that alterations in B cells are closely associated with disease progression. Further analysis identified seven distinct B cell subpopulations, with immune responses and the tumor microenvironment exerting significant influence on their dynamics. Mendelian randomization analysis revealed key genes, CD83 and CRIP2, that are linked to the risk of RA. Subsequent investigation demonstrated strong associations between these genes and immune cell populations. GSEA and GSVA analyses showed that CD83 is involved in pathways related to allograft rejection and antigen processing, while CRIP2 is associated with interactions of extracellular matrix receptors and the IL-17 signaling pathway. Additionally, immunometabolism pathway analysis highlighted potential therapeutic targets and underlying mechanisms.
DISCUSSION
The findings suggest that B cells play a major role in the RA immune microenvironment and identify CD83 and CRIP2 as potential biomarkers and therapeutic targets. CD83 may contribute to RA through immune regulation, antigen presentation, and inflammatory signaling, whereas CRIP2 may be involved in metal ion homeostasis, cellular stress responses, and immune-related pathological processes. Immune infiltration analyses further indicate that these genes are closely associated with immune-cell activity in RA. Overall, the study provides new insight into RA pathogenesis and supports the potential clinical relevance of CD83 and CRIP2, although further experimental and clinical validation is required.
CONCLUSION
This study offers valuable understanding about RA pathogenesis and identifies probable diagnostic biomarkers as well as therapeutic targets (CD83 and CRIP2), which could improve our awareness of the illness and help with formulating more successful care plans.
Shi-Kai Chen, Han-Yu Wang, Cheng Wang et al.· Current Medicinal Chemistry· 0 citations
This integrated genetic and clinical analysis found no robust evidence that genetic liability to AIHT materially affects overall endometriosis risk or vice versa in the datasets analyzed, and no clear clinical association between confirmed endometriosis and AIHT or thyroid autoimmunity.
Jia-Wei Shi, Wei-Jie Jiang, Hui Chen et al.· Frontiers in Endocrinology· 0 citations
Background Psoriasis is a chronic immune-mediated inflammatory skin disease driven by complex interactions between genetic susceptibility, immune dysregulation, and keratinocyte dysfunction. Although genome-wide association studies have identified numerous risk loci, most studies have focused on genetic associations rather than causal inference, limiting the identification of effective therapeutic targets. We employed an integrative multi-omics strategy to identify causal genes and potential therapeutic candidates for psoriasis. Methods We integrated psoriasis genome-wide association study (GWAS), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) datasets to perform two-sample Mendelian Randomization (MR) analyses and prioritize high-confidence causal genes. Most genetic datasets were derived from European-ancestry populations. Single-cell transcriptomic analysis was then used to determine their cell-type-specific expression patterns. Finally, drug-target prediction and molecular docking were applied to identify potential therapeutic compounds. Results Integrative MR analyses indicated that genetically predicted higher BLMH expression and plasma protein levels were significantly associated with reduced psoriasis risk, with colocalization analysis supporting shared causal variants at the BLMH locus. Single-cell transcriptomics further demonstrated keratinocyte-enriched expression of BLMH and marked downregulation in psoriatic lesional skin. Drug screening using DSigDB combined with molecular docking identified tamibarotene as a potential BLMH-binding compound with favorable docking affinity. In vitro experiments showed that tamibarotene treatment was associated with increased BLMH expression and reduced KRT16, IL6, and IL8 expression in the M5-stimulated HaCaT model. Conclusion Our integrative multi-omics analysis nominates BLMH as a keratinocyte-enriched protective candidate gene in psoriasis and suggests tamibarotene as a potential repurposed compound for further investigation. However, the experimental validation remains preliminary, and further mechanistic, in vivo, and translational studies are required to validate these findings.
Rui Shen, Bin-Yi Ran, Jia-Zheng Liu et al.· Journal of Inflammation Rese...· 0 citations
OBJECTIVES
Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities.
METHODS
We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation.
RESULTS
SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets.
CONCLUSIONS
Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.
Jin Li, Hui-Qi Qu, Michael E. March et al.· Annals of the Rheumatic Dise...· 0 citations
Background/Objectives: Although genetic studies have linked immune phenotypes with anxiety, broad Mendelian randomization (MR) screens require explicit multiple-testing control. We reappraised 1753 reported immune-cell-trait-to-anxiety inverse-variance-weighted (IVW) association records available in the analysis tables and assessed the chromosome 20 signal that includes CD40. Methods: The reported records were derived from the 731-trait Sardinian flow-cytometry GWAS of Orrù et al. and were evaluated across one UK Biobank and three FinnGen anxiety phenotypes; outcome-specific Benjamini–Hochberg false-discovery-rate (FDR) correction was applied to the available analysis table. The leading locus was examined using bulk and single-cell expression quantitative trait locus annotations, two-sample MR, summary-data-based MR (SMR), HEIDI tests, and regional colocalization results. Results: Of 1753 tests, 120 were nominally significant, and 21 were retained after outcome-specific FDR correction (14 for UK Biobank anxiety and 7 for FinnGen all anxiety; none for generalized or phobic anxiety). B-cell and regulatory/CD4 T-cell traits were common among retained associations, and several B-cell traits mapped to variants at the CD40 locus. For FinnGen all anxiety disorders, monocyte instruments gave a positive estimate (beta = 0.00418, p = 9.25 × 10−4), whereas three naïve B-cell instruments gave a negative estimate (beta = −0.0520, p = 2.64 × 10−4). Monocyte SMR was null (p = 0.542). Naïve B-cell SMR was nominally significant (p = 0.00537), but HEIDI could not be calculated. Regional colocalization was weak in both cell contexts (PP.H4 = 0.0205 and 0.00272). Conclusions: The post-selection locus follow-up prioritizes a chromosome 20 immune locus but does not establish CD40-mediated regulation of anxiety. Because the upstream screen was not regenerated from source GWAS files and complete per-instrument F-statistics were unavailable, all findings are exploratory. CD40 remains a testable candidate for ancestry-matched fine-mapping and cell-state-specific validation.
Lu-Wei Wang, Yi-Fan Duan, Bo Sun et al.· Genes· 0 citations
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