Lu Haojie, Zhang Jinhui, Jiang Zhou, Zhang Meng, Wang Ting, Zhao Huashuo, Zeng Ping
Department of Epidemiology and Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, China.
Center for Medical Statistics and Data Analysis, School of Public Health, Xuzhou Medical University, Xuzhou, China.
Front Genet. 2021 Mar 18;12:656545. doi: 10.3389/fgene.2021.656545. eCollection 2021.
Clinical and epidemiological studies have suggested systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are comorbidities and common genetic etiologies can partly explain such coexistence. However, shared genetic determinations underlying the two diseases remain largely unknown.
Our analysis relied on summary statistics available from genome-wide association studies of SLE ( = 23,210) and RA ( = 58,284). We first evaluated the genetic correlation between RA and SLE through the linkage disequilibrium score regression (LDSC). Then, we performed a multiple-tissue eQTL (expression quantitative trait loci) weighted integrative analysis for each of the two diseases and aggregated association evidence across these tissues via the recently proposed harmonic mean -value (HMP) combination strategy, which can produce a single well-calibrated -value for correlated test statistics. Afterwards, we conducted the pleiotropy-informed association using conjunction conditional FDR (ccFDR) to identify potential pleiotropic genes associated with both RA and SLE.
We found there existed a significant positive genetic correlation ( = 0.404, = 6.01E-10) via LDSC between RA and SLE. Based on the multiple-tissue eQTL weighted integrative analysis and the HMP combination across various tissues, we discovered 14 potential pleiotropic genes by ccFDR, among which four were likely newly novel genes (i.e., , , , and ). The SNP effect sizes of these pleiotropic genes were typically positively dependent, with an average correlation of 0.579. Functionally, these genes were implicated in multiple auto-immune relevant pathways such as inositol phosphate metabolic process, membrane and glucagon signaling pathway.
This study reveals common genetic components between RA and SLE and provides candidate associated loci for understanding of molecular mechanism underlying the comorbidity of the two diseases.
临床和流行病学研究表明，系统性红斑狼疮（SLE）和类风湿关节炎（RA）存在合并症，常见的遗传病因可部分解释这种共存现象。然而，这两种疾病共同的遗传决定因素在很大程度上仍不清楚。
我们的分析依赖于系统性红斑狼疮（n = 23,210）和类风湿关节炎（n = 58,284）全基因组关联研究的汇总统计数据。我们首先通过连锁不平衡评分回归（LDSC）评估类风湿关节炎和系统性红斑狼疮之间的遗传相关性。然后，我们对这两种疾病分别进行多组织eQTL（表达数量性状位点）加权综合分析，并通过最近提出的调和均值P值（HMP）组合策略汇总这些组织中的关联证据，该策略可以为相关检验统计量生成单个校准良好的P值。之后，我们使用联合条件FDR（ccFDR）进行多效性关联分析，以识别与类风湿关节炎和系统性红斑狼疮相关的潜在多效性基因。
我们通过LDSC发现类风湿关节炎和系统性红斑狼疮之间存在显著的正遗传相关性（r = 0.404，P = 6.01E - 10）。基于多组织eQTL加权综合分析以及跨各种组织的HMP组合，我们通过ccFDR发现了14个潜在的多效性基因，其中四个可能是新的基因（即，，，和）。这些多效性基因的SNP效应大小通常呈正相关，平均相关性为0.579。在功能上，这些基因涉及多个自身免疫相关途径，如肌醇磷酸代谢过程、膜和胰高血糖素信号通路。
本研究揭示了类风湿关节炎和系统性红斑狼疮之间的共同遗传成分，并为理解这两种疾病合并症的分子机制提供了候选相关位点。
