Bivariate genome-wide association study of circulating fibrinogen and C-reactive protein levels.

IF 5.5 2区医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-09-17 DOI:10.1016/j.jtha.2024.08.021

Julie Hahn, Gerard Temprano-Sagrera, Natalie R Hasbani, Symen Ligthart, Abbas Dehghan, Alisa S Wolberg, Nicholas L Smith, Maria Sabater-Lleal, Alanna C Morrison, Paul S de Vries

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Abstract

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.

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循环纤维蛋白原和 C 反应蛋白水平的双变量全基因组关联研究。

背景：纤维蛋白原和C反应蛋白（CRP）在炎症通路中发挥着重要作用，并且在先前发表的GWAS中报告了多个共同的遗传位点，这突显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更多与纤维蛋白原和CRP具有褶皱相关性的基因位点：我们进行了一项双变量 GWAS，利用先前发表的 GWAS 的汇总统计，确定了进一步的多向遗传位点，其中纤维蛋白原（n=120,246）来自基因组流行病学中的心脏和衰老研究队列（CHARGE）联合会，由欧洲血统样本和 CRP（n=363,228）来自英国生物库，包括 5 个不同的人群。主要分析使用 metaUSAT 和 N-GWAMA 进行。我们对新的 CRP 关联进行了复制，以使用 CRP 的独立 GWAS（n=148,164）检验研究结果的稳健性。我们还进行了共定位分析，以比较两个性状的已鉴定位点与基因型-组织表达（GTEx）数据的关联：结果：我们发现了 87 个在 metaUSAT 和 N-GWAMA 之间重叠的多向性位点，包括 23 个以前已知的纤维蛋白原或 CRP 位点、58 个纤维蛋白原的新位点以及 6 个纤维蛋白原和 CRP 的新位点。总体而言，这两个性状共有 30 个多效应基因座和新基因座，其中 7 个基因座有共定位的迹象，分别位于 ZZZ3、NR1I2、RP11-72L22.1、MICU1、ARL14EP、SOCS2 和 PGM5 或其附近。在这 30 个位点中，有 13 个位点在独立的 CRP GWAS 中与 CRP 重现：结论：双变量 GWAS 发现了纤维蛋白原和 CRP 的其他相关基因位点。这项分析表明，纤维蛋白原和 CRP 与许多多效应位点具有共同的遗传结构。

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来源期刊

Journal of Thrombosis and Haemostasis 医学-外周血管病

CiteScore

24.30

自引率

3.80%

发文量

321

审稿时长

1 months

期刊介绍： The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.