Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers.

IF 1.5 4区生物学 Q4 GENETICS & HEREDITY

Annals of Human Genetics Pub Date : 2026-09-11 DOI:10.1111/ahg.70058

Xiaojian Feng, Zhixian Pan, Guoping Liu

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引用次数: 0

Abstract

Background: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear.

Aims: We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers.

Materials and methods: We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping.

Results: A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues.

Discussion: These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways.

Conclusion: Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.

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基因组结构方程模型识别炎症性关节炎表型和生物标志物之间共享的炎症遗传维度。

背景：炎性关节炎（IA），包括类风湿关节炎（RA）、银屑病关节炎（PsA）和痛风，具有由c反应蛋白（CRP）和白细胞介素-6 （IL-6）指示的全身性炎症特征，但其共同遗传基础的程度尚不清楚。目的：我们旨在描述IA表型和炎症生物标志物之间的共享遗传结构。材料和方法：我们应用基因组结构方程模型（genomic SEM）对RA、PsA、痛风、CRP和IL-6的GWAS汇总统计，拟合单一共同因子，并进行多变量GWAS，随后进行精细定位、转录组全关联、基因分析、途径富集、细胞类型和空间定位。结果：单因子拟合（CFI = 0.990, SRMR = 0.045）。多变量GWAS在10个独立的先导位点中鉴定出56个全基因组显著snp，包括一个新信号。精细定位PTPN22附近的高可信度变异，CRP基因簇和精确相关位点。基因水平分析集中在DCLRE1B、PTPN22、IL6R、NLRP3和HNF1A上，途径富集与炎症小体组装和代谢-炎症重叠有关。细胞类型的富集突出了髓系群体，并将空间定位信号定位到肺、肾、粘膜上皮和胃肠道组织。讨论：这些结果描述了IA表型和生物标志物之间共同的炎症遗传维度，锚定在免疫、炎症体、细胞因子受体和代谢途径中。总之，这些发现提供了一个有价值的框架，优先考虑候选基因和细胞背景，为未来的研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Human Genetics 生物-遗传学

CiteScore

4.20

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： Annals of Human Genetics publishes material directly concerned with human genetics or the application of scientific principles and techniques to any aspect of human inheritance. Papers that describe work on other species that may be relevant to human genetics will also be considered. Mathematical models should include examples of application to data where possible. Authors are welcome to submit Supporting Information, such as data sets or additional figures or tables, that will not be published in the print edition of the journal, but which will be viewable via the online edition and stored on the website.