A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythernatosus
A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythernatosus
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DOI：
10.1136/annrheumdis-2016-209436
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发表时间：
2017-01-01
影响因子：
27.4
通讯作者：
Martin, Javier
中科院分区：
文献类型：
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作者：
Marquez, Ana;Vidal-Bralo, Laura;Martin, Javier
在过去的几年中，全基因组关联研究（GWASs）已经确定了一些常见的类风湿关节炎（RA）和系统性红斑狼疮（SLE）的遗传危险因素。然而，到目前为止，这两种免疫介导疾病之间的遗传重叠尚未得到彻底的研究。本研究的目的是确定类风湿关节炎和SLE之间共有的其他风险位点。方法对RA（3911例，4083例对照）和SLE（2237例，6315例对照）的GWAS数据进行了大规模荟萃分析。研究人员选择发现阶段的顶层相关多态性在其他数据集中进行复制，这些数据集包括13 641例RA病例和31 921例对照，以及1957例SLE患者和4588例对照。结果rs9603612基因变异位于已确定的RA易感位点COG6基因附近，在包括发现集和复制集的组合分析中达到全基因组显著性（p值=2.95E-13）。基因座分析表明，相关多态性是影响COG6基因表达的调控变异。此外，蛋白质-蛋白质相互作用和基因本体富集分析表明，与特定生物过程，特别是I型干扰素信号通路存在重叠。最后，遗传相关和多基因风险评分分析显示RA和SLE之间存在交叉表型关联。总之，通过包括两种疾病的GWAS数据集的荟萃分析，我们确定了RA和SLE之间共有的一个新的风险位点。这项研究首次对这两种复杂疾病之间的遗传重叠进行了全面的大规模分析。
Objectives During the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE.Methods We performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls.Results The rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E-13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein-protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE.Conclusions In conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.