Florian Thibord1, Ci Song1, Jack Pattee2, Benjamin A T Rodriguez1, Ming-Huei Chen1, Christopher J O'Donnell1,3, Marcus E Kleber4,5, Graciela E Delgado4, Xiuqing Guo6, Jie Yao6, Kent D Taylor6, Ayse Bilge Ozel7, Jennifer A Brody8, Barbara McKnight9, Beata Gyorgy10, Eleanor Simonsick11, Hampton L Leonard11, Germán D Carrasquilla12, Marta Guindo-Martinez12, Angela Silveira13, Gerard Temprano-Sagrera14, Lisa R Yanek15, Diane M Becker15, Rasika A Mathias15,16, Lewis C Becker15,17, Laura M Raffield18, Tuomas O Kilpeläinen12, Niels Grarup12, Oluf Pedersen12, Torben Hansen12, Allan Linneberg19, Anders Hamsten13, Hugh Watkins20, Maria Sabater-Lleal13,14, Mike A Nalls11, David-Alexandre Trégouët10,21, Pierre-Emmanuel Morange22, Bruce M Psaty8, Russel P Tracy23, Nicholas L Smith8,24,25,26, Karl C Desch27, Mary Cushman23, Jerome I Rotter6, Paul S de Vries28, Nathan D Pankratz29, Aaron R Folsom30, Alanna C Morrison28, Winfried März4,31, Weihong Tang30, Andrew D Johnson1. 1. The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA. 2. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. 3. U.S. Department of Veterans Affairs, Boston, Massachusetts, USA. 4. Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 5. SYNLAB MVZ Humangenetik Mannheim GmbH, Mannheim, Germany. 6. Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA. 7. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. 8. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA. 9. Department of Biostatistics, University of Washington, Seattle, Washington, USA. 10. INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France. 11. National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. 12. Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. 13. Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine and Karolinska University Hospital Solna, Stockholm, Sweden. 14. Genomics of Complex Diseases, Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain. 15. GeneSTAR Research Program, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 16. Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 17. Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 18. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 19. Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark. 20. Radcliffe Department of Medicine, University of Oxford, Oxford, UK. 21. INSERM, BPH, Univ. Bordeaux, Bordeaux, France. 22. INSERM, INRAE, Aix-Marseille Univ, Marseille, France. 23. Department of Pathology and Laboratory Medicine & Department of Medicine, Vermont Center on Cardiovascular and Brain Health, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA. 24. Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, Washington, USA. 25. Department of Epidemiology, University of Washington, Seattle, Washington, USA. 26. Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle,, Washington, USA. 27. Department of Pediatrics, Cell and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA. 28. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. 29. Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. 30. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. 31. Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
Abstract
BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer. OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach. METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing. RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10-8 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10-4 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels. CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.
BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer. OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach. METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing. RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10-8 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10-4 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels. CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.