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

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

doi:10.1016/j.jtha.2024.08.021

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

J Thromb Haemost. 2024 Sep 17:S1538-7836(24)00544-0. doi: 10.1016/j.jtha.2024.08.021. Online ahead of print.

Authors

Affiliations

¹ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address: Julie.M.Hahn@uth.tmc.edu.
² Genomics of Complex Diseases Unit, Institut d'Investigació Biomèdica Sant Pau, IIB Sant Pau, Barcelona, Spain.
³ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁴ Department of Intensive Care, Antwerp University Hospital, Edegem, Belgium.
⁵ UK Dementia Research Institute at Imperial College London, London, United Kingdom; Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
⁶ Pathology and Laboratory Medicine and University of North Carolina Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁷ Department of Epidemiology, University of Washington, Seattle, Washington, USA; Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA; Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, Washington, USA.
⁸ Genomics of Complex Diseases Unit, Institut d'Investigació Biomèdica Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine and Karolinska University Hospital Solna, Stockholm, Sweden.
⁹ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address: Paul.S.DeVries@uth.tmc.edu.

PMID: 39299614
DOI: 10.1016/j.jtha.2024.08.021

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: C-reactive protein; bivariate GWAS; colocalization; fibrinogen.