Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Jennifer E Huffman^{1

2}, Jayna Nicholas³, Julie Hahn⁴, Adam S Heath⁴, Laura M Raffield³, Lisa R Yanek⁵, Jennifer A Brody⁶, Florian Thibord⁷, Laura Almasy⁸, Traci M Bartz⁹, Lawrence F Bielak¹⁰, Russell P Bowler¹¹, Germán D Carrasquilla^{12

13}, Daniel I Chasman¹⁴, Ming-Huei Chen⁷, David B Emmert¹⁵, Mohsen Ghanbari¹⁶, Jeffrey Haessler¹⁷, Jouke-Jan Hottenga¹⁸, Marcus E Kleber^{19

20}, Ngoc-Quynh Le²¹, Jiwon Lee²², Joshua P Lewis²³, Ruifang Li-Gao²⁴, Jian'an Luan²⁵, Anni Malmberg²⁶, Massimo Mangino^{27

28}, Riccardo E Marioni²⁹, Angel Martinez-Perez^{30

31}, Nathan Pankratz³², Ozren Polasek³³, Anne Richmond³⁴, Benjamin A T Rodriguez⁷, Jerome I Rotter³⁵, Maristella Steri³⁶, Pierre Suchon^{37

38}, Stella Trompet³⁹, Stefan Weiss⁴⁰, Marjan Zare^{41

42}, Paul Auer⁴³, Michael H Cho⁴⁴, Paraskevi Christofidou²⁷, Gail Davies⁴⁵, Eco de Geus¹⁸, Jean-François Deleuze⁴⁶, Graciela E Delgado²⁰, Lynette Ekunwe⁴⁷, Nauder Faraday⁴⁸, Martin Gögele¹⁵, Andreas Greinacher⁴⁹, He Gao^{42

50}, Tom Howard⁵¹, Peter K Joshi⁵², Tuomas O Kilpeläinen¹², Jari Lahti²⁶, Allan Linneberg⁵³, Silvia Naitza³⁶, Raymond Noordam³⁹, Ferran Paüls-Vergés²¹, Stephen S Rich⁵⁴, Frits R Rosendaal²⁴, Igor Rudan⁵², Kathleen A Ryan²³, Juan Carlos Souto^{30

31

55}, Frank J A van Rooij¹⁶, Heming Wang²², Wei Zhao^{10

56}, Lewis C Becker⁵, Andrew Beswick⁵⁷, Michael R Brown⁴, Brian E Cade²², Harry Campbell⁵², Kelly Cho^{2

58}, James D Crapo¹¹, Joanne E Curran⁵⁹, Moniek P M de Maat⁶⁰, Margaret Doyle⁶¹, Paul Elliott^{42

50

62}, James S Floyd⁶³, Christian Fuchsberger¹⁵, Niels Grarup¹², Xiuqing Guo³⁵, Sarah E Harris⁴⁵, Lifang Hou⁶⁴, Ivana Kolcic³³, Charles Kooperberg¹⁷, Cristina Menni²⁷, Matthias Nauck⁶⁵, Jeffrey R O'Connell²³, Valeria Orrù⁶⁶, Bruce M Psaty^{6

67

68}, Katri Räikkönen²⁶, Jennifer A Smith^{10

56}, Jose Manuel Soria^{30

31}, David J Stott⁶⁹, Astrid van Hylckama Vlieg²⁴, Hugh Watkins⁷⁰, Gonneke Willemsen¹⁸, Peter W F Wilson^{71

72

73}, Yoav Ben-Shlomo⁷⁴, John Blangero⁵⁹, Dorret Boomsma¹⁸, Simon R Cox⁴⁵, Abbas Dehghan^{42

50

62}, Johan G Eriksson^{75

76

77}, Edoardo Fiorillo⁶⁶, Myriam Fornage⁷⁸, Torben Hansen¹², Caroline Hayward³⁴, M Arfan Ikram¹⁶, J Wouter Jukema^{79

80}, Sharon L R Kardia¹⁰, Leslie A Lange⁸¹, Winfried März⁸², Rasika A Mathias⁵, Braxton D Mitchell^{23

83}, Dennis O Mook-Kanamori^{24

84}, Pierre-Emmanuel Morange^{37

38}, Oluf Pedersen¹², Peter P Pramstaller¹⁵, Susan Redline^{22

85}, Alexander Reiner¹⁷, Paul M Ridker¹⁴, Edwin K Silverman⁴⁴, Tim D Spector²⁷, Uwe Völker⁴⁰, Nicholas J Wareham²⁵, James F Wilson^{34

52}, Jie Yao³⁵, David-Alexandre Trégouët⁸⁶, Andrew D Johnson⁷, Alisa S Wolberg⁸⁷, Paul S de Vries⁴, Maria Sabater-Lleal^{30

31

88}, Alanna C Morrison⁴, Nicholas L Smith^{67

89

90}

Affiliations

¹ Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, Palo Alto, CA.
² MAVERIC, VA Boston Healthcare System, Boston, MA.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁴ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
⁵ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
⁷ National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA.
⁸ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA.
⁹ Department of Biostatistics, University of Washington, Seattle, WA.
¹⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
¹¹ National Jewish Health, Denver, CO.
¹² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹⁵ Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy.
¹⁶ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁷ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA.
¹⁸ Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹⁹ SYNLAB MVZ für Humangenetik Mannheim, Mannheim, Germany.
²⁰ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
²¹ Unit of Genomics of Complex Disease, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain.
²² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²³ Department of Medicine, University of Maryland, Baltimore, MD.
²⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
²⁶ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
²⁷ Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
²⁸ National Institute for Health and Care Research Biomedical Research Centre, Guy's and St Thomas' Foundation Trust, London, United Kingdom.
²⁹ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
³⁰ Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain.
³¹ Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain.
³² Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.
³³ Faculty of Medicine, University of Split, Split, Croatia.
³⁴ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
³⁵ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
³⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato-Cagliari, Italy.
³⁷ Centre de Recherche en Cardiovascular et Nutrition, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Aix Marseille University, Marseille, France.
³⁸ Laboratory of Haematology, La Timone Hospital, Marseille, France.
³⁹ Section of Gerontology and Geriatrics, Department of Internal Medicin, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁰ Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, German Center for Cardiovascular Research, Partner Site Greifswald, University Medicine Greifswald, Greifswald, Germany.
⁴¹ Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
⁴³ Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI.
⁴⁴ Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
⁴⁵ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
⁴⁶ Centre National de Recherche en Génomique Humaine, Commissariat a l'Energie Atomique et aux Energies Alternatives, Université Paris-Saclay, Evry, France.
⁴⁷ Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS.
⁴⁸ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
⁴⁹ Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
⁵⁰ Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
⁵¹ Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
⁵² Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
⁵³ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
⁵⁴ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
⁵⁵ Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁵⁶ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI.
⁵⁷ Translational Health Sciences, University of Bristol, Bristol, United Kingdom.
⁵⁸ Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA.
⁵⁹ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
⁶⁰ Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁶¹ Department of Pathology and Laboratory Medicine, The University of Vermont Larner College of Medicine, Colchester, VT.
⁶² United Kingdom-Dementia Research Institute, Imperial College London, London, United Kingdom.
⁶³ Departments of Medicine and Epidemiology, University of Washington, Seattle, WA.
⁶⁴ Department of Preventive Medicine, Northwestern University, Chicago, IL.
⁶⁵ Institute of Clinical Chemistry and Laboratory Medicine, German Center for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany, University Medicine Greifswald, Greifswald, Germany.
⁶⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy.
⁶⁷ Department of Epidemiology, University of Washington, Seattle, WA.
⁶⁸ Department of Health Systems and Population Health, University of Washington, Seattle, WA.
⁶⁹ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
⁷⁰ Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
⁷¹ VA Atlanta Healthcare System, Decatur, GA.
⁷² Division of Cardiology, Emory University School of Medicine, Atlanta, GA.
⁷³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.
⁷⁴ Poulation Health Sciences, University of Bristol, Bristol, United Kingdom.
⁷⁵ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
⁷⁶ Folkhälsan Research Centre, Helsinki, Finland.
⁷⁷ Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
⁷⁸ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.
⁷⁹ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁸⁰ Netherlands Heart Institute, Utrecht, The Netherlands.
⁸¹ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
⁸² Synlab Academy, Synlab Holding Deutschland GmbH, and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁸³ Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.
⁸⁴ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
⁸⁵ Department of Medicine, Beth Israel Deaconness Medical Center, Boston, MA.
⁸⁶ Bordeaux Population Health Research Center, INSERM UMR 1219, University of Bordeaux, Bordeaux, France.
⁸⁷ Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁸⁸ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden.
⁸⁹ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA.
⁹⁰ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA.

PMID: 39226462
PMCID: PMC11600029 (available on 2025-11-21)
DOI: 10.1182/blood.2023022596

Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Jennifer E Huffman et al. Blood. 2024.

. 2024 Nov 21;144(21):2248-2265.

doi: 10.1182/blood.2023022596.

Authors

Affiliations

¹ Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, Palo Alto, CA.
² MAVERIC, VA Boston Healthcare System, Boston, MA.
³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁴ Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
⁵ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
⁷ National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA.
⁸ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA.
⁹ Department of Biostatistics, University of Washington, Seattle, WA.
¹⁰ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
¹¹ National Jewish Health, Denver, CO.
¹² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹⁵ Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Bolzano, Italy.
¹⁶ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁷ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA.
¹⁸ Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹⁹ SYNLAB MVZ für Humangenetik Mannheim, Mannheim, Germany.
²⁰ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
²¹ Unit of Genomics of Complex Disease, Institut d'Investigació Biomèdica Sant Pau, Barcelona, Spain.
²² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²³ Department of Medicine, University of Maryland, Baltimore, MD.
²⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
²⁶ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
²⁷ Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom.
²⁸ National Institute for Health and Care Research Biomedical Research Centre, Guy's and St Thomas' Foundation Trust, London, United Kingdom.
²⁹ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
³⁰ Unit of Genomics of Complex Disease, Institut de Recerca Sant Paul, Barcelona, Spain.
³¹ Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain.
³² Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.
³³ Faculty of Medicine, University of Split, Split, Croatia.
³⁴ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
³⁵ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
³⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato-Cagliari, Italy.
³⁷ Centre de Recherche en Cardiovascular et Nutrition, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Aix Marseille University, Marseille, France.
³⁸ Laboratory of Haematology, La Timone Hospital, Marseille, France.
³⁹ Section of Gerontology and Geriatrics, Department of Internal Medicin, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁰ Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, German Center for Cardiovascular Research, Partner Site Greifswald, University Medicine Greifswald, Greifswald, Germany.
⁴¹ Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
⁴³ Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI.
⁴⁴ Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
⁴⁵ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
⁴⁶ Centre National de Recherche en Génomique Humaine, Commissariat a l'Energie Atomique et aux Energies Alternatives, Université Paris-Saclay, Evry, France.
⁴⁷ Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS.
⁴⁸ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
⁴⁹ Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.
⁵⁰ Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
⁵¹ Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
⁵² Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
⁵³ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
⁵⁴ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
⁵⁵ Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁵⁶ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI.
⁵⁷ Translational Health Sciences, University of Bristol, Bristol, United Kingdom.
⁵⁸ Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA.
⁵⁹ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
⁶⁰ Department of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁶¹ Department of Pathology and Laboratory Medicine, The University of Vermont Larner College of Medicine, Colchester, VT.
⁶² United Kingdom-Dementia Research Institute, Imperial College London, London, United Kingdom.
⁶³ Departments of Medicine and Epidemiology, University of Washington, Seattle, WA.
⁶⁴ Department of Preventive Medicine, Northwestern University, Chicago, IL.
⁶⁵ Institute of Clinical Chemistry and Laboratory Medicine, German Center for Cardiovascular Research, Partner Site Greifswald, Greifswald, Germany, University Medicine Greifswald, Greifswald, Germany.
⁶⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Lanusei, Italy.
⁶⁷ Department of Epidemiology, University of Washington, Seattle, WA.
⁶⁸ Department of Health Systems and Population Health, University of Washington, Seattle, WA.
⁶⁹ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
⁷⁰ Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
⁷¹ VA Atlanta Healthcare System, Decatur, GA.
⁷² Division of Cardiology, Emory University School of Medicine, Atlanta, GA.
⁷³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.
⁷⁴ Poulation Health Sciences, University of Bristol, Bristol, United Kingdom.
⁷⁵ Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
⁷⁶ Folkhälsan Research Centre, Helsinki, Finland.
⁷⁷ Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
⁷⁸ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.
⁷⁹ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁸⁰ Netherlands Heart Institute, Utrecht, The Netherlands.
⁸¹ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
⁸² Synlab Academy, Synlab Holding Deutschland GmbH, and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁸³ Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.
⁸⁴ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
⁸⁵ Department of Medicine, Beth Israel Deaconness Medical Center, Boston, MA.
⁸⁶ Bordeaux Population Health Research Center, INSERM UMR 1219, University of Bordeaux, Bordeaux, France.
⁸⁷ Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁸⁸ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden.
⁸⁹ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA.
⁹⁰ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA.

PMID: 39226462
PMCID: PMC11600029 (available on 2025-11-21)
DOI: 10.1182/blood.2023022596

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.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: L.R. is a consultant for the TOPMed Administrative Coordinating Center (through WeStat). R.L.-G. is a part-time consultant for Metabolon, Inc. M.C. has received grant support from Bayer. B.P. serves on the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson. In the past 3 years, E.K.S. has received grant support from Bayer. The remaining authors declare no competing financial interests.

A complete list of the members of the VA Million Veteran Program and the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium appears in the supplemental Data.

Update of

Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.
Huffman JE, Nicolas J, Hahn J, Heath AS, Raffield LM, Yanek LR, Brody JA, Thibord F, Almasy L, Bartz TM, Bielak LF, Bowler RP, Carrasquilla GD, Chasman DI, Chen MH, Emmert DB, Ghanbari M, Haessle J, Hottenga JJ, Kleber ME, Le NQ, Lee J, Lewis JP, Li-Gao R, Luan J, Malmberg A, Mangino M, Marioni RE, Martinez-Perez A, Pankratz N, Polasek O, Richmond A, Rodriguez BA, Rotter JI, Steri M, Suchon P, Trompet S, Weiss S, Zare M, Auer P, Cho MH, Christofidou P, Davies G, de Geus E, Deleuze JF, Delgado GE, Ekunwe L, Faraday N, Gögele M, Greinacher A, He G, Howard T, Joshi PK, Kilpeläinen TO, Lahti J, Linneberg A, Naitza S, Noordam R, Paüls-Vergés F, Rich SS, Rosendaal FR, Rudan I, Ryan KA, Souto JC, van Rooij FJ, Wang H, Zhao W, Becker LC, Beswick A, Brown MR, Cade BE, Campbell H, Cho K, Crapo JD, Curran JE, de Maat MP, Doyle M, Elliott P, Floyd JS, Fuchsberger C, Grarup N, Guo X, Harris SE, Hou L, Kolcic I, Kooperberg C, Menni C, Nauck M, O'Connell JR, Orrù V, Psaty BM, Räikkönen K, Smith JA, Soria JM, Stott DJ, van Hylckama Vlieg A, Watkins H, Willemsen G, Wilson P, Ben-Shlomo Y, Blangero J, Boomsma D, Cox SR, Dehghan A, Eriksson JG, Fiorillo E, Fornage M, Hansen T, Hayward C, Ikram MA, J… See abstract for full author list ➔ Huffman JE, et al. medRxiv [Preprint]. 2023 Jun 12:2023.06.07.23291095. doi: 10.1101/2023.06.07.23291095. medRxiv. 2023. Update in: Blood. 2024 Nov 21;144(21):2248-2265. doi: 10.1182/blood.2023022596. PMID: 37398003 Free PMC article. Updated. Preprint.

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Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Affiliations

Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

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