Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles-Reference-Cited by-同舟云学术

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

Published:2024-09-03 Issue: Volume: Page:
ISSN:0006-4971
Container-title:Blood Journal
language:en
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Author:

Huffman Jennifer E.¹^ORCID,Nicholas Jayna²^ORCID,Hahn Julie³^ORCID,Heath Adam S⁴^ORCID,Raffield Laura M⁵^ORCID,Yanek Lisa R⁶^ORCID,Brody Jennifer A⁷^ORCID,Thibord Florian⁵^ORCID,Almasy Laura⁸,Bartz Traci M⁷,Bielak Lawrence F⁹,Bowler Russell P¹⁰,Carrasquilla German D.¹¹^ORCID,Chasman Daniel I.⁷^ORCID,Chen Ming-Huei⁷^ORCID,Emmert David B¹²^ORCID,Ghanbari Mohsen⁵^ORCID,Haessler Jeffrey⁷,Hottenga Jouke J⁷,Kleber Marcus E⁷,Le Ngoc-Quynh¹³,Lee Jiwon¹⁴^ORCID,Lewis Joshua P⁷,Li-Gao Ruifang⁵^ORCID,Luan Jian'an¹⁵^ORCID,Malmberg Anni Liisi¹⁶,Mangino Massimo⁷^ORCID,Marioni Riccardo⁵,Martinez-Perez Angel⁵^ORCID,Pankratz Nathan⁷,Polasek Ozren⁷,Richmond Anne¹⁷,Rodriguez Benjamin A.T.⁵,Rotter Jerome I¹⁸,Steri Maristella⁷^ORCID,Suchon Pierre¹⁹,Trompet Stella²⁰,Weiss Stefan²¹^ORCID,Zare Marjan²²,Auer Paul L.¹⁸^ORCID,Cho Michael¹⁸^ORCID,Christofidou Paraskevi²³,Davies Gail⁷^ORCID,de Geus Eco JC⁵^ORCID,Deleuze Jean-François²⁴^ORCID,Delgado Graciela E⁷,Ekunwe Lynette⁷,Faraday Nauder⁷,Gogele Martin¹²^ORCID,Greinacher Andreas¹⁸^ORCID,Gao He²²,Howard Tom E.⁷^ORCID,Joshi Peter K⁷^ORCID,Kilpeläinen Tuomas O⁵,Lahti Jari⁷^ORCID,Linneberg Allan⁷^ORCID,Naitza Silvia²⁵^ORCID,Noordam Raymond⁷,Vergés Ferran Paüls¹³^ORCID,Rich Stephen S⁷,Rosendaal Frits R.⁷^ORCID,Rudan Igor⁵,Ryan Kathleen A⁷^ORCID,Souto Juan Carlos Carlos⁷^ORCID,van Rooij Frank J.A.²⁶^ORCID,Wang Heming¹⁴^ORCID,Zhao Wei⁹,Becker Lewis⁷,Beswick Andrew⁷^ORCID,Brown Michael R⁵,Cade Brian⁷^ORCID,Campbell Harry⁷^ORCID,Cho Kelly²⁷,Crapo James⁷,Curran Joanne²⁸,de Maat Moniek P.M.²⁹^ORCID,Doyle Margaret F.³⁰,Elliott Paul³¹^ORCID,Floyd James S³²,Fuchsberger Christian¹²,Grarup Niels¹¹^ORCID,Guo Xiuqing⁷^ORCID,Harris Sarah⁵^ORCID,Hou Lifang⁷,Kolcic Ivana⁷^ORCID,Kooperberg Charles³³,Menni Cristina²³,Nauck Matthias²¹^ORCID,O'Connell Jeffrey R⁷,Orru Valeria³⁴^ORCID,Psaty Bruce M⁷,Räikkönen Katri⁷,Smith Jennifer A⁹,Soria Jose Manuel⁷,Stott David³⁵^ORCID,van Hylckama Vlieg Astrid³⁶,Watkins Hugh³⁷,Willemsen Gonneke³⁸,Wilson Peter WF³⁹,Ben-Shlomo Yoav⁴⁰,Blangero John⁴¹,Boomsma Dorret⁴²^ORCID,Cox Simon R¹⁷^ORCID,Dehghan Abbas³¹^ORCID,Eriksson Johan G¹⁶,Fiorillo Edoardo⁴³^ORCID,Fornage Myriam⁴^ORCID,Hansen Torben¹¹^ORCID,Hayward Caroline¹⁷^ORCID,Ikram Mohammad Arfan⁴⁴,Jukema J. Wouter³⁶^ORCID,Kardia Sharon⁹,Lange Leslie⁴⁵,Maerz Winfried⁴⁶^ORCID,Mathias Rasika⁴⁷,Mitchell Braxton D⁴⁸^ORCID,Mook-Kanamori Dennis O³⁶,Morange Pierre-Emmanuel⁴⁹,Pedersen Oluf¹¹^ORCID,Pramstaller Peter P.¹²^ORCID,Redline Susan⁵⁰,Reiner Alex P⁵¹,Ridker Paul M⁵⁰,Silverman Edwin K⁵⁰,Spector Tim D⁵²,Volker Uwe²¹^ORCID,Wareham Nick¹⁵^ORCID,Wilson James¹⁷^ORCID,Yao Jie⁵³,Tregouet David-Alexandre⁵⁴^ORCID,Johnson Andrew D.⁵⁵^ORCID,Wolberg Alisa S.²^ORCID,de Vries Paul S.⁴,Sabater-Lleal Maria⁵⁶^ORCID,Morrison Alanna⁵⁷,Smith Nicholas L.⁷

Affiliation:

1. Palo Alto VA Institute for Research, VA Palo Alto Heath Care System, United States

2. University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States

3. School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States

4. University of Texas Health Science Center at Houston, Houston, Texas, United States

5. Karolinska Institutet, Center for Molecular Medicine, Sweden

6. Johns Hopkins Medical Institutions, Baltimore, Maryland, United States

7. Department of Veterans Affairs Office of Research and Development, United States

8. University of Pennsylvania, Philadelphia, Pennsylvania, United States

9. University of Michigan, Ann Arbor, Michigan, United States

10. National Jewish Health, Denver, Colorado, United States

11. University of Copenhagen, Copenhagen, Denmark

12. Eurac Research, Bolzano, Italy

13. Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain

14. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

15. University of Cambridge, Cambridge, United Kingdom

16. University of Helsinki, Helsinki, Finland

17. University of Edinburgh, Edinburgh, United Kingdom

18. The Framingham Heart Study, United States

19. AP-HM, Marseille, France

20. LUMC, Leiden, Netherlands

21. University Medicine Greifswald, Greifswald, Germany

22. School of Public Health, Imperial College London, London, United Kingdom

23. Kings College London, London, United Kingdom

24. CEA Fontenay-Aux-Roses, Evry, France

25. IRGB, CNR, Monserrato-Cagliari, Italy

26. Erasmus University Medical Center, Rotterdam, Netherlands

27. VA Boston Healthcare System, Boston, Massachusetts, United States

28. School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, United States

29. Erasmus Medical Center Rotterdam, Rotterdam, Netherlands

30. Larner College of Medicine at the University of Vermont, Colchester, Vermont, United States

31. Imperial College London, London, United Kingdom

32. University of Washington, Seattle, Washington, United States

33. FHCRC, Seattle, United States

34. Institute for Genetic and Biomedical Research, National Research Council, Lanusei, Italy

35. University of Glasgow, Glasgow, United Kingdom

36. Leiden University Medical Center, Leiden, Netherlands

37. University of Oxford, Oxford, United Kingdom

38. Vrije Universiteit Amsterdam, Amsterdam, Netherlands

39. Atlanta VA Health Care System, Decatur, Georgia, United States

40. University of Bristol, Bristol, United Kingdom

41. University of Texas Rio Grande Valley, Brownsville, United States

42. Vrije Universiteit, Amsterdam, Amsterdam, Netherlands

43. Consiglio Nazionale delle Ricerche, Lanusei, Italy

44. Erasmus MC, Rotterdam, Netherlands

45. University of Colorado, Anschutz Medical Campus, Aurora, Colorado, United States

46. Synlab MVZ Heidelberg, Eppelheim, Germany

47. Johns Hopkins University, Baltimore, Maryland, United States

48. University of Maryland, Baltimore, Maryland, United States

49. CHU Timone - Marseille France, Marseille, France

50. Brigham and Women's Hospital, Boston, Massachusetts, United States

51. Fred Hutchinson Cancer Center, Seattle, Washington, United States

52. king's College London, London, United Kingdom

53. The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States

54. INSERM UMR 1219, Bordeaux Population Health Research Center, Bordeaux, France

55. National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts, United States

56. Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain

57. University of Texas at Houston Health Science Center, Houston, Texas, United States

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 provides 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 NHLBI'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 (CHARGE) 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, four are driven by common variants of small effect with reported 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 two conditionally distinct, non-coding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA), contains 7 distinct signals, including one 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. -

Publisher

American Society of Hematology

Link

https://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023022596/2240821/blood.2023022596.pdf