Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
Jennifer E. Huffman, Jayna Nicholas, 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, Jeffrey Haessler, 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, Benjamin A.T. Rodriguez, 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 P.M. 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
Abstract
ABSTRACT: Genetic 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 provide 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 National Heart, Lung, and Blood Institute'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 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, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). 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.