Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Genomics of Complex Diseases Unit, Institut d'Investigació Biomèdica Sant Pau, IIB Sant Pau, Barcelona, Spain.
J Thromb Haemost. 2024 Dec;22(12):3448-3459. doi: 10.1016/j.jtha.2024.08.021. Epub 2024 Sep 17.
BACKGROUND: Fibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP. OBJECTIVES: To identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS. METHODS: We performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, consisting of European ancestry samples and CRP (n = 363 228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n = 148 164). We also performed colocalization analysis to compare the associations in identified loci for the 2 traits and Genotype-Tissue Expression data. RESULTS: We identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS. CONCLUSION: Bivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci.
背景:纤维蛋白原和 C 反应蛋白 (CRP) 在炎症途径中发挥重要作用,并且在先前发表的全基因组关联研究 (GWAS) 中共享多个遗传位点,这突出了它们共同的遗传背景。利用共同的生物学特性可能会发现与纤维蛋白原和 CRP 均相关的其他多效性遗传位点。
目的:通过使用多性状 GWAS 将两种表型整合到双变量 GWAS 中,确定与纤维蛋白原和 CRP 均具有多效性且相关的新型遗传变异。
方法:我们进行了双变量 GWAS,以使用来自基因组流行病学队列的心脏和衰老研究中的汇总统计数据来识别进一步的多效性遗传位点,该队列由欧洲血统样本组成,以及来自 UK Biobank 的 CRP (n=363228),其中包括 5 个不同的人群组。主要分析使用 metaUSAT 和 N-GWAMA 进行。我们使用 CRP 的独立 GWAS (n=148164) 对新发现的 CRP 关联进行了复制,以测试结果的稳健性。我们还进行了共定位分析,以比较 2 种性状和组织表达数据中鉴定出的位点的关联。
结果:我们确定了 87 个在 metaUSAT 和 N-GWAMA 之间重叠的多效性位点,包括 23 个已知与纤维蛋白原或 CRP 相关的位点、58 个纤维蛋白原的新位点和 6 个纤维蛋白原和 CRP 的新位点。总的来说,有 30 个与两种性状相关的多效性和新的位点,其中 7 个显示出共定位的证据,位于 ZZZ3、NR1I2、RP11-72L22.1、MICU1、ARL14EP、SOCS2 和 PGM5 内或附近。在这 30 个位点中,有 13 个在 CRP 的独立 CRP GWAS 中得到了复制。
结论:双变量 GWAS 确定了纤维蛋白原和 CRP 的其他相关位点。该分析表明,纤维蛋白原和 CRP 具有许多多效性遗传位点的共同遗传结构。
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