Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
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.
Authors
- Winfried März (ORCID: https://orcid.org/0000-0001-6083-8946)
- Anni Malmberg (ORCID: https://orcid.org/0000-0003-4347-1788)
- Peter W.F. Wilson (ORCID: https://orcid.org/0000-0002-5653-7056)
- Traci M. Bartz (ORCID: https://orcid.org/0000-0003-3403-8763)
- Laura Almasy (ORCID: https://orcid.org/0000-0002-9184-8124)
- Bruce M. Psaty (ORCID: https://orcid.org/0000-0002-7278-2190)
- Charles Kooperberg (ORCID: https://orcid.org/0000-0002-7986-8560)
- John Blangero (ORCID: https://orcid.org/0000-0001-6250-5723)
- Lynette Ekunwe
- Frank J.A. van Rooij (ORCID: https://orcid.org/0000-0002-8600-9852)
- J. Wouter Jukema (ORCID: https://orcid.org/0000-0002-3246-8359)
- Maristella Steri (ORCID: https://orcid.org/0000-0001-5869-3872)
- Katri Räikkönen (ORCID: https://orcid.org/0000-0003-3124-3470)
- Joshua P. Lewis (ORCID: https://orcid.org/0000-0002-4107-6066)
- Johan G. Eriksson (ORCID: https://orcid.org/0000-0002-2516-2060)
- Pierre Suchon (ORCID: https://orcid.org/0000-0001-8845-9163)
- Jennifer E. Huffman (ORCID: https://orcid.org/0000-0002-9672-2491)
- Lifang Hou (ORCID: https://orcid.org/0000-0003-4877-0031)
- Marjan Zare (ORCID: https://orcid.org/0000-0002-0199-3230)
- Daniel I. Chasman (ORCID: https://orcid.org/0000-0003-3357-0862)
- Kathleen A. Ryan (ORCID: https://orcid.org/0000-0003-1158-8455)
- Raymond Noordam (ORCID: https://orcid.org/0000-0001-7801-809X)
- Russell Paul Bowler (ORCID: https://orcid.org/0000-0003-4651-363X)
- Anne Richmond (ORCID: https://orcid.org/0000-0002-9504-510X)
- Michael H. Cho (ORCID: https://orcid.org/0000-0002-4907-1657)
- Ming‐Huei Chen (ORCID: https://orcid.org/0000-0003-3551-8726)
- Gail Davies (ORCID: https://orcid.org/0000-0003-1120-7026)
- Ivana Kolčić (ORCID: https://orcid.org/0000-0001-7918-6052)
- Brian E. Cade (ORCID: https://orcid.org/0000-0003-1424-0673)
- Jian’an Luan
- Braxton D. Mitchell (ORCID: https://orcid.org/0000-0003-4920-4744)
- Juan Carlos Souto (ORCID: https://orcid.org/0000-0003-2092-5142)
- Jouke‐Jan Hottenga (ORCID: https://orcid.org/0000-0002-5668-2368)
- Jari M. T. Lahti (ORCID: https://orcid.org/0000-0002-4310-5297)
- Nathan Pankratz (ORCID: https://orcid.org/0000-0001-5958-693X)
- David J. Stott
- Frits R. Rosendaal (ORCID: https://orcid.org/0000-0003-2558-7496)
- Dennis O. Mook‐Kanamori (ORCID: https://orcid.org/0000-0002-0182-5122)
- Hugh Watkins (ORCID: https://orcid.org/0000-0002-5287-9016)
- Florian Thibord (ORCID: https://orcid.org/0000-0003-2229-8322)
- Christian Fuchsberger (ORCID: https://orcid.org/0000-0002-5918-8947)
- Paul Elliott (ORCID: https://orcid.org/0000-0002-7511-5684)
- Edwin K. Silverman (ORCID: https://orcid.org/0000-0002-3641-3822)
- Jayna Nicholas (ORCID: https://orcid.org/0000-0001-9821-6384)
- David Emmert (ORCID: https://orcid.org/0000-0001-8149-1072)
- Sarah E. Harris (ORCID: https://orcid.org/0000-0002-4941-5106)
- Gonneke Willemsen (ORCID: https://orcid.org/0000-0003-3755-0236)
- Igor Rudan (ORCID: https://orcid.org/0000-0001-6993-6884)
- Matthias Nauck (ORCID: https://orcid.org/0000-0002-6678-7964)
- Massimo Mangino (ORCID: https://orcid.org/0000-0002-2167-7470)
- Jerome I. Rotter (ORCID: https://orcid.org/0000-0001-7191-1723)
- Sharon L. R. Kardia (ORCID: https://orcid.org/0000-0002-9853-3379)
- Laura M. Raffield (ORCID: https://orcid.org/0000-0002-7892-193X)
- José Manuel Soria (ORCID: https://orcid.org/0000-0002-6226-4293)
- Jeffrey R. O’Connell (ORCID: https://orcid.org/0000-0002-7046-6688)
- Martin Gögele (ORCID: https://orcid.org/0000-0003-4785-4348)
- Caroline Hayward (ORCID: https://orcid.org/0000-0002-9405-9550)
- Yoav Ben‐Shlomo (ORCID: https://orcid.org/0000-0001-6648-3007)
- Kelly Cho (ORCID: https://orcid.org/0000-0003-1727-7076)
- Jean‐François Deleuze (ORCID: https://orcid.org/0000-0002-5358-4463)
- Margaret F. Doyle (ORCID: https://orcid.org/0000-0001-6769-5386)
- Susan Redline (ORCID: https://orcid.org/0000-0002-6585-1610)
- James D. Crapo (ORCID: https://orcid.org/0000-0002-1262-5230)
- Moniek P.M. de Maat (ORCID: https://orcid.org/0000-0001-7749-334X)
- Nauder Faraday (ORCID: https://orcid.org/0000-0002-7397-9980)
- Ozren Polašek (ORCID: https://orcid.org/0000-0002-5765-1862)
- Allan Linneberg (ORCID: https://orcid.org/0000-0002-0994-0184)
- Lewis C. Becker (ORCID: https://orcid.org/0000-0003-4805-3403)
- Paul S. de Vries (ORCID: https://orcid.org/0000-0003-0964-0111)
- Tom E. Howard (ORCID: https://orcid.org/0000-0002-4550-278X)
- Andrew D Beswick (ORCID: https://orcid.org/0000-0002-7032-7514)
- Astrid van Hylckama Vlieg (ORCID: https://orcid.org/0000-0001-7386-1168)
- James F. Wilson (ORCID: https://orcid.org/0000-0001-5751-9178)
- Tuomas O. Kilpeläinen (ORCID: https://orcid.org/0000-0002-8349-3028)
- Adam S. Heath (ORCID: https://orcid.org/0000-0002-5909-9055)
- Andrew D. Johnson (ORCID: https://orcid.org/0000-0001-6369-5178)
- James S. Floyd (ORCID: https://orcid.org/0000-0002-0365-9041)
- Jennifer A. Smith (ORCID: https://orcid.org/0000-0002-3575-5468)
- Paul Livermore Auer (ORCID: https://orcid.org/0000-0003-1735-8044)
- Marcus E. Kleber (ORCID: https://orcid.org/0000-0003-0663-7275)
- Maria Sabater‐Lleal (ORCID: https://orcid.org/0000-0002-0128-379X)
- Ángel Martínez-Pérez (ORCID: https://orcid.org/0000-0002-5934-1454)
- Valeria Orrù (ORCID: https://orcid.org/0000-0002-6047-4625)
- Niels Grarup (ORCID: https://orcid.org/0000-0001-5526-1070)
- Rasika A. Mathias (ORCID: https://orcid.org/0000-0002-2282-9042)
- Alisa S. Wolberg (ORCID: https://orcid.org/0000-0002-2845-2303)
- Lisa R. Yanek (ORCID: https://orcid.org/0000-0001-7117-1075)
- Riccardo E. Marioni (ORCID: https://orcid.org/0000-0003-4430-4260)
- Mohsen Ghanbari (ORCID: https://orcid.org/0000-0002-9476-7143)
- Oluf Pedersen (ORCID: https://orcid.org/0000-0002-3321-3972)
- Peter Paul Pramstaller (ORCID: https://orcid.org/0000-0002-9831-8302)
- Jennifer A. Brody (ORCID: https://orcid.org/0000-0001-8509-148X)
- Ruifang Li‐Gao (ORCID: https://orcid.org/0000-0003-0650-1351)
- Germán D. Carrasquilla (ORCID: https://orcid.org/0000-0002-7147-9421)
- Harry J. Campbell (ORCID: https://orcid.org/0000-0002-6169-6262)
- Stephen S. Rich (ORCID: https://orcid.org/0000-0003-3872-7793)
- David‐Alexandre Trégouët (ORCID: https://orcid.org/0000-0001-9084-7800)
- Simon R. Cox (ORCID: https://orcid.org/0000-0003-4036-3642)
- Michael R. Brown (ORCID: https://orcid.org/0000-0002-5235-9037)
- Stefan Weiß (ORCID: https://orcid.org/0000-0002-3553-4315)
- Pierre‐Emmanuel Morange (ORCID: https://orcid.org/0000-0002-9065-722X)
- Andreas Greinacher (ORCID: https://orcid.org/0000-0001-8343-7336)
- Eco J. C. de Geus (ORCID: https://orcid.org/0000-0001-6022-2666)
- Lawrence F. Bielak (ORCID: https://orcid.org/0000-0002-3443-8030)
- Cristina Menni (ORCID: https://orcid.org/0000-0001-9790-0571)
- Dorret Irene Boomsma (ORCID: https://orcid.org/0000-0002-7099-7972)
- Alanna C. Morrison (ORCID: https://orcid.org/0000-0001-6381-4296)
- Ngoc‐Quynh Le (ORCID: https://orcid.org/0000-0002-7797-4925)
- Silvia Naitza (ORCID: https://orcid.org/0000-0002-0108-757X)
- Abbas Dehghan (ORCID: https://orcid.org/0000-0001-6403-016X)
- Peter K. Joshi (ORCID: https://orcid.org/0000-0002-6361-5059)
- Uwe Völker (ORCID: https://orcid.org/0000-0002-5689-3448)
- Julie Hahn (ORCID: https://orcid.org/0000-0002-9757-1648)
- Xiuqing Guo (ORCID: https://orcid.org/0000-0002-5264-5068)
- Joanne E. Curran (ORCID: https://orcid.org/0000-0002-6898-155X)
- He Gao (ORCID: https://orcid.org/0000-0003-2516-6288)
- Stella Trompet (ORCID: https://orcid.org/0000-0001-5006-0528)
- Paraskevi Christofidou (ORCID: https://orcid.org/0000-0002-5809-6557)
- Jiwon Lee (ORCID: https://orcid.org/0000-0002-4079-7494)
- Myriam Fornage (ORCID: https://orcid.org/0000-0003-0677-8158)
- Jie Yao (ORCID: https://orcid.org/0000-0001-5812-6624)
- Torben Hansen (ORCID: https://orcid.org/0000-0001-8748-3831)
- Nicholas J. Wareham (ORCID: https://orcid.org/0000-0003-1422-2993)
- Heming Wang (ORCID: https://orcid.org/0000-0002-1486-7495)
- Wei Zhao (ORCID: https://orcid.org/0000-0003-0319-1722)
- Edoardo Fiorillo (ORCID: https://orcid.org/0000-0002-8690-4988)
- Benjamin A.T. Rodriguez (ORCID: https://orcid.org/0000-0001-7104-1262)
- Graciela E. Delgado
- M. Arfan Ikram
- Ferran Paüls-Vergés (ORCID: https://orcid.org/0000-0003-2225-4194)
- Paul M. Ridker
- Jeffrey Haessler
- Tim D. Spector
- Nicholas L. Smith
- Alexander P. Reiner
- Leslie A. Lange
Institutions
- University of Vermont (US)
- Northwestern University (US)
- University of North Carolina at Chapel Hill (US)
- University of Copenhagen (DK)
- University of Maryland, Baltimore (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Eurac Research (IT)
- Children's Hospital of Philadelphia (US)
- University of Helsinki (FI)
- Harvard University (US)
- Johns Hopkins University (US)
- Kaiser Permanente Washington Health Research Institute (US)
- Emory University (US)
- Université de Bordeaux (FR)
- Inserm (FR)
- National University of Singapore (SG)
- King's College London (GB)
- Shiraz University of Medical Sciences (IR)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- University of Washington (US)
- Medical College of Wisconsin (US)
- Aix-Marseille Université (FR)
- Heidelberg University (DE)
- University of Cambridge (GB)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- University of Michigan (US)
- Universitätsmedizin Greifswald (DE)
- Johns Hopkins Medicine (US)
- Leiden University Medical Center (NL)
- Novo Nordisk Foundation (DK)
- Frederiksberg Hospital (DK)
- Instituto de Salud Carlos III (ES)
- UCLA Medical Center (US)
- VA Boston Healthcare System (US)
- Hospital de Sant Pau (ES)
- Erasmus MC (NL)
- VA Office of Research and Development (US)
- University Hospital Heidelberg (DE)
- The University of Texas Rio Grande Valley (US)
- Edinburgh Cancer Research (GB)
- Karolinska Institutet (SE)
- University of Mississippi Medical Center (US)
- National Jewish Health (US)
- Public Health England (GB)
- University of Bristol (GB)
- University of Oxford (GB)
- Centre National de Recherche en Génomique Humaine (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Fred Hutch Cancer Center (US)
- Center for Clinical Research and Prevention (DK)
- Netherlands Heart Institute (NL)
- Bordeaux Population Health (FR)
- National Heart, Lung, and Blood Institute (US)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Institute of Genetic and Biomedical Research (IT)
- Institute for Biomedicine (IT)
- Framingham Heart Study (US)
- UK Dementia Research Institute (GB)
- Synlab (Germany) (DE)
- University of Minnesota Medical Center (US)
- Praxis für Humangenetik (DE)
- Brown Foundation (US)
- Centre for Global Health Research (CA)
- Atlanta VA Health Care System (US)
- University Medical Centre Mannheim (DE)
- MRC Epidemiology Unit (GB)
- Institute of Genetics and Cancer (GB)
- Hôpital de la Timone (FR)
- Harbor–UCLA Medical Center (US)
- Institut de Recerca Sant Pau (ES)
- Imperial College London (GB)
- University of Virginia (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Glasgow (GB)
- Vrije Universiteit Amsterdam (NL)
- Medical Research Council (GB)
- The University of Texas Health Science Center at Houston (US)
- University of Colorado Denver (US)
- University of Split (HR)
- University of Edinburgh (GB)
Publication Details
- Journal
- Blood
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1182/blood.2023022596
- Citations
- 13
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 7.15