Zhou Rou, Lin Xu, Li Ding-You, Wang Xia-Fang, Greenbaum Jonathan, Chen Yuan-Cheng, Zeng Chun-Ping, Lu Jun-Min, Ao Zeng-Xing, Peng Lin-Ping, Bai Xiao Chun, Shen Jie, Deng Hong-Wen
Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
Department of Gastroenterology, Children's Mercy Kansas City, University of Missouri Kansas City School of Medicine, Kansas City, MO, United States of America.
PLoS One. 2017 Aug 30;12(8):e0183842. doi: 10.1371/journal.pone.0183842. eCollection 2017.
There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.
骨质疏松症（OP）与类风湿性关节炎（RA）之间存在共病现象。先前的研究已分别确定了这两种表型的一些遗传风险因素；然而，它们仅占潜在总遗传变异的一小部分。在此，我们试图识别与OP和/或RA相关的其他常见基因位点。条件错误发现率（cFDR）方法能够检测这两种相关表型的其他遗传因素（各自的以及共同的多效性因素）。我们收集并分析了由大型多中心全基因组关联研究（GWAS）提供的关于股骨颈（FNK）骨密度（骨质疏松症的主要风险因素）（n = 53,236）和RA（n = 80,799）的汇总统计数据。条件分位数 - 分位数（Q - Q）图可分别评估与FNK骨密度和RA相关的单核苷酸多态性（SNP）的富集情况。此外，我们使用联合cFDR（ccFDR）识别了FNK骨密度和RA之间的共享位点。当对RA进行条件Q - Q分析时，我们发现FNK骨密度的p值有很强的富集，反之亦然。我们识别出30个先前在OP或RA的GWAS中未报道过的与OP - RA相关的新的多效性位点，其中18个位于先前报道在免疫系统和骨骼健康中起重要作用的主要组织相容性复合体（MHC）区域。我们分别识别出一些OP和RA的特定新的多基因因素，并识别出30个与OP - RA相关的新的多效性位点。这些发现可能提供新的病理生物学见解，并为OP和RA患者的药物开发提出新的靶点和途径。
