Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London WC2R 2LS, UK.
Hum Mol Genet. 2022 Aug 23;31(16):2810-2819. doi: 10.1093/hmg/ddac061.
Rheumatoid arthritis (RA) and osteoporosis (OP) are two comorbid complex inflammatory conditions with evidence of shared genetic background and causal relationships. We aimed to clarify the genetic architecture underlying RA and various OP phenotypes while additionally considering an inflammatory component, C-reactive protein (CRP). Genome-wide association study summary statistics were acquired from the GEnetic Factors for OSteoporosis Consortium, Cohorts for Heart and Aging Research Consortium and UK Biobank. Mendelian randomization (MR) was used to detect the presence of causal relationships. Colocalization analysis was performed to determine shared genetic variants between CRP and OP phenotypes. Analysis of pleiotropy between traits owing to shared causal single nucleotide polymorphisms (SNPs) was performed using PL eiotropic A nalysis under CO mposite null hypothesis (PLACO). MR analysis was suggestive of horizontal pleiotropy between RA and OP traits. RA was a significant causal risk factor for CRP (β = 0.027, 95% confidence interval = 0.016-0.038). There was no evidence of CRP→OP causal relationship, but horizontal pleiotropy was apparent. Colocalization established shared genomic regions between CRP and OP, including GCKR and SERPINA1 genes. Pleiotropy arising from shared causal SNPs revealed through the colocalization analysis was all confirmed by PLACO. These genes were found to be involved in the same molecular function 'protein binding' (GO:0005515) associated with RA, OP and CRP. We identified three major components explaining the epidemiological relationship among RA, OP and inflammation: (1) Pleiotropy explains a portion of the shared genetic relationship between RA and OP, albeit polygenically; (2) RA contributes to CRP elevation and (3) CRP, which is influenced by RA, demonstrated pleiotropy with OP.
类风湿关节炎（RA）和骨质疏松症（OP）是两种共患的复杂炎症性疾病，有证据表明它们具有共同的遗传背景和因果关系。我们旨在阐明 RA 和各种 OP 表型的遗传结构，同时考虑炎症成分 C 反应蛋白（CRP）。从骨质疏松症遗传因素联盟、心脏和衰老研究联盟队列以及英国生物库中获得了全基因组关联研究汇总统计数据。使用孟德尔随机化（MR）来检测因果关系的存在。进行共定位分析以确定 CRP 和 OP 表型之间的共享遗传变异。使用基于复合零假设的多效性分析下共同因果单核苷酸多态性（SNP）的性状间多效性分析（PLACO）来分析由于共享因果 SNP 引起的性状间多效性。MR 分析表明 RA 和 OP 性状之间存在水平多效性。RA 是 CRP 的显著因果风险因素（β=0.027，95%置信区间=0.016-0.038）。没有 CRP→OP 因果关系的证据，但水平多效性明显。共定位确定了 CRP 和 OP 之间的共享基因组区域，包括 GCKR 和 SERPINA1 基因。通过共定位分析揭示的源于共享因果 SNP 的多效性均通过 PLACO 得到证实。这些基因被发现参与了与 RA、OP 和 CRP 相关的相同分子功能“蛋白质结合”（GO:0005515）。我们确定了三个主要成分，解释了 RA、OP 和炎症之间的流行病学关系：（1）多效性解释了 RA 和 OP 之间部分共同遗传关系，尽管是多基因的；（2）RA 导致 CRP 升高；（3）CRP 受 RA 影响，与 OP 具有多效性。
