Faculty, Staff and Student Publications

Language

English

Publication Date

12-1-2024

Journal

Journal of Thrombosis and Haemostasis

DOI

10.1016/j.jtha.2024.08.021

PMID

39299614

PMCID

PMC12009655

PubMedCentral® Posted Date

12-1-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Genome-Wide Association Study, Fibrinogen, C-Reactive Protein, Phenotype, Male, Polymorphism, Single Nucleotide, Female, Genetic Pleiotropy, Middle Aged, Aged, Biomarkers, Genetic Predisposition to Disease, Adult, Bivariate GWAS, Fibrinogen, C-reactive protein, Colocalization

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yes

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