Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
Authors: Huffman Jennifer E. , Nicholas Jayna , Hahn Julie , Heath Adam S. , Raffield Laura M. , Yanek Lisa R. , Brody Jennifer A. , Thibord Florian , Almasy Laura , Bartz Traci M. , Bielak Lawrence F. , Bowler Russell P. , Carrasquilla Germán D. , Chasman Daniel I. , Chen Ming-Huei , Emmert David B. , Ghanbari Mohsen , Haessler Jeffrey , Hottenga Jouke-Jan , Kleber Marcus E. , Le Ngoc-Quynh , Lee Jiwon , Lewis Joshua P. , Li-Gao Ruifang , Luan Jian'an , Malmberg Anni , Mangino Massimo , Marioni Riccardo E. , Martinez-Perez Angel , Pankratz Nathan , Polasek Ozren , Richmond Anne , Rodriguez Benjamin A. T. , Rotter Jerome I. , Steri Maristella , Suchon Pierre , Trompet Stella , Weiss Stefan , Zare Marjan , Auer Paul , Cho Michael H. , Christofidou Paraskevi , Davies Gail , de Geus Eco , Deleuze Jean-François , Delgado Graciela E. , Ekunwe Lynette , Faraday Nauder , Gögele Martin , Greinacher Andreas , Gao He , Howard Tom , Joshi Peter K. , Kilpeläinen Tuomas O. , Lahti Jari , Linneberg Allan , Naitza Silvia , Noordam Raymond , Paüls-Vergés Ferran , Rich Stephen S. , Rosendaal Frits R. , Rudan Igor , Ryan Kathleen A. , Souto Juan Carlos , van Rooij Frank J. A. , Wang Heming , Zhao Wei , Becker Lewis C. , Beswick Andrew , Brown Michael R. , Cade Brian E. , Campbell Harry , Cho Kelly , Crapo James D. , Curran Joanne E. , de Maat Moniek P. M. , Doyle Margaret , Elliott Paul , Floyd James S. , Fuchsberger Christian , Grarup Niels , Guo Xiuqing , Harris Sarah E. , Hou Lifang , Kolcic Ivana , Kooperberg Charles , Menni Cristina , Nauck Matthias , O'Connell Jeffrey R. , Orrù Valeria , Psaty Bruce M. , Räikkönen Katri , Smith Jennifer A. , Soria Jose Manuel , Stott David J. , van Hylckama Vlieg Astrid , Watkins Hugh , Willemsen Gonneke , Wilson Peter W. F. , Ben-Shlomo Yoav , Blangero John , Boomsma Dorret , Cox Simon R. , Dehghan Abbas , Eriksson Johan G. , Fiorillo Edoardo , Fornage Myriam , Hansen Torben , Hayward Caroline , Ikram M. Arfan , Jukema J. Wouter , Kardia Sharon L. R. , Lange Leslie A. , März Winfried , Mathias Rasika A. , Mitchell Braxton D. , Mook-Kanamori Dennis O. , Morange Pierre-Emmanuel , Pedersen Oluf , Pramstaller Peter P. , Redline Susan , Reiner Alexander , Ridker Paul M. , Silverman Edwin K. , Spector Tim D. , Völker Uwe , Wareham Nicholas J. , Wilson James F. , Yao Jie , Trégouët David-Alexandre , Johnson Andrew D. , Wolberg Alisa S. , de Vries Paul S. , Sabater-Lleal Maria , Morrison Alanna C. , Smith Nicholas L. 
Published: September 2024

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.