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Get Free AccessGenetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( SERPINA1, ZFP36L2 , and TLR10) signals contain predicted deleterious missense variants. Two loci, SOCS3 and HPN , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( FGG;FGB;FGA ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation. Key Points Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel). Sufficient power achieved to identify signal driven by African population variant. Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
Jennifer E. Huffman, Jayna Nicolas, Julie Hahn, Adam S. Heath, Laura M. Raffield, Lisa R. Yanek, Jennifer A. Brody, Florian Thibord, Laura Almasy, Traci M. Bartz, Lawrence F. Bielak, Russell P. Bowler, Germán D Carrasquilla, Daniel I. Chasman, Ming‐Huei Chen, David Emmert, Mohsen Ghanbari, Jeffery Haessle, Jouke‐Jan Hottenga, Marcus E. Kleber, Ngoc‐Quynh Le, Jiwon Lee, Joshua P. Lewis, Ruifang Li‐Gao, Jian’an Luan, Anni Malmberg, Massimo Mangino, Riccardo E. Marioni, Ángel Martínez-Pérez, Nathan Pankratz, Ozren Polašek, Anne Richmond, Blanca Rodríguez, Jerome I. Rotter, Maristella Steri, Pierre Suchon, Stella Trompet, Stefan Weiß, Marjan Zare, Paul L. Auer, Michael H. Cho, Paraskevi Christofidou, Gail Davies, Eco J. C. de Geus, Jean-François Deleuze, Graciela E. Delgado, Lynette Ekunwe, Nauder Faraday, Martin Gögele, Andreas Greinacher, He Gao, Tom E. Howard, Peter K. Joshi, Tuomas O. Kilpeläinen, Jari Lahti, Allan Linneberg, Silvia Naitza, Raymond Noordam, Ferran Paüls-Vergés, Stephen S. Rich, Frits R. Rosendaal, Igor Rudan, Kathleen A. Ryan, Juan Carlos Souto, Frank J.A. van Rooij, Heming Wang, Wei Zhao, Lewis C. Becker, Andrew D Beswick, Michael R. Brown, Brian E. Cade, Harry Campbell, Kelly Cho, James D. Crapo, Joanne E. Curran, Moniek PM de Maat, Margaret F. Doyle, Paul Elliott, James S. Floyd, Christian Fuchsberger, Niels Grarup, Xiuqing Guo, Sarah E. Harris, Lifang Hou, Ivana Kolčić, Charles Kooperberg, Cristina Menni, Matthias Nauck, Jeffrey R. O’Connell, Valeria Orrù, Bruce M. Psaty, Katri Räikkönen, Jennifer A. Smith, José Manuel Soria, David J. Stott, Astrid van Hylckama Vlieg, Hugh Watkins, Gonneke Willemsen, Peter W.F. Wilson, Yoav Ben‐Shlomo (2023). Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. medRxiv (Cold Spring Harbor Laboratory), DOI: 10.1101/2023.06.07.23291095.
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Type
Preprint
Year
2023
Authors
100
Datasets
0
Total Files
0
Language
English
Journal
medRxiv (Cold Spring Harbor Laboratory)
DOI
10.1101/2023.06.07.23291095
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