Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
Por:
Huffman, JE, Nicholas, 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, Haessler, 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, BAT, 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, Gao, H, 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, FJA, Wang, HM, Zhao, W, Becker, LC, Beswick, A, Brown, MR, Cade, BE, Campbell, H, Cho, K, Crapo, JD, Curran, JE, de Maat, MPM, Doyle, M, Elliott, P, Floyd, JS, Fuchsberger, C, Grarup, N, Guo, XQ, Harris, SE, Hou, LF, Kolcic, I, Kooperberg, C, Menni, C, Nauck, M, O'Connell, JR, Orrú, V, Psaty, BM, Räikkönen, K, Smith, JA, Soria, JM, Stott, DJ, Vlieg, AV, Watkins, H, Willemsen, G, Wilson, PWF, Ben-Shlomo, Y, Blangero, J, Boomsma, D, Cox, SR, Dehghan, A, Eriksson, JG, Fiorillo, E, Fornage, M, Hansen, T, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lange, LA, März, W, Mathias, RA, Mitchell, BD, Mook-Kanamori, DO, Morange, PE, Pedersen, O, Pramstaller, PP, Redline, S, Reiner, A, Ridker, PM, Silverman, EK, Spector, TD, Völker, U, Wareham, NJ, Wilson, JF, Yao, J, Trégouët, DA, Johnson, AD, Wolberg, AS, de Vries, PS, Sabater-Lleal, M, Morrison, AC, Smith, NL
Publicada:
21 nov 2024
Resumen:
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 (MAF(AFR) = 0.180; MAF(EUR) = 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.
Filiaciones:
Huffman, JE:
VA Palo Alto Heath Care Syst, Palo Alto VA Inst Res, Palo Alto, CA USA
VA Boston Healthcare Syst, MAVERIC, Boston, MA USA
Nicholas, J:
Univ North Carolina, Dept Genet, Chapel Hill, NC USA
Heath, AS:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol, Ctr Human Genet, Houston, TX USA
Yanek, LR:
Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD USA
Brody, JA:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Thibord, F:
Natl Heart Lung & Blood Inst, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Almasy, L:
Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA USA
Bartz, TM:
Univ Washington, Dept Biostat, Seattle, WA USA
Bielak, LF:
Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI USA
Bowler, RP:
Natl Jewish Hlth, Denver, CO USA
Carrasquilla, GD:
Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark
Karolinska Inst, Inst Environm Med, Stockholm, Sweden
Chasman, DI:
Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA
Chen, MH:
Natl Heart Lung & Blood Inst, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Emmert, DB:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Ghanbari, M:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Haessler, J:
Fred Hutchinson Canc Ctr, Div Publ Hlth Sci, Seattle, WA USA
Hottenga, JJ:
Vrije Univ, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands
Kleber, ME:
Synlab MVZ Humangenet Mannheim, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Le, NQ:
Inst Invest Biomed Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Lee, J:
Harvard Med Sch, Brigham & Womens Hosp, Med, Boston, MA USA
Lewis, JP:
Univ Maryland, Med, Baltimore, MD USA
Li-Gao, R:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Luan, J:
Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England
Malmberg, A:
Univ Helsinki, Dept Psychol & Logoped, Helsinki, Finland
Mangino, M:
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Guys & St Thomas Fdn Trust, Natl Inst Hlth & Care Res Biomed Res Ctr, London, England
Marioni, RE:
Univ Edinburgh, Inst Genet & Canc, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland
Martinez-Perez, A:
Inst Recerca Sant Paul, Unit Genom Complex Dis, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis, Madrid, Spain
Pankratz, N:
Univ Minnesota, Dept Lab Med & Pathol, Med Sch, Minneapolis, MN USA
Polasek, O:
Univ Split, Fac Med, Split, Croatia
Richmond, A:
Univ Edinburgh, Inst Genet & Canc, Med Res Council, Human Genet Unit, Edinburgh, Midlothian, Scotland
Rodriguez, BAT:
Natl Heart Lung & Blood Inst, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Rotter, JI:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Steri, M:
CNR, Ist Ric Genet & Biomed, Monserrato, Italy
Suchon, P:
Aix Marseille Univ, Inst Natl Rech Agr, Ctr Rech Cardio Vasc & Nutr, INSERM, Marseille, France
La Timone Hosp, Lab Haematol, Marseille, France
Trompet, S:
Leiden Univ Med Ctr, Dept Internal Medicin, Sect Gerontol & Geriatr, Leiden, Netherlands
Weiss, S:
Univ Med Greifswald, Dept Funct Genom, German Ctr Cardiovasc Res, Partner Site Greifswald,Interfac Inst Genet & Fun, Greifswald, Germany
Zare, M:
Shiraz Univ Med Sci, Med Res Ctr, Shiraz, Iran
Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England
Auer, P:
Med Coll Wisconsin, Inst Hlth & Equity, Div Biostat, Milwaukee, WI USA
Med Coll Wisconsin, Canc Ctr, Milwaukee, WI USA
Cho, MH:
Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA
Harvard Med Sch, Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA USA
Christofidou, P:
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Davies, G:
Univ Edinburgh, Dept Psychol, Lothian Birth Cohorts, Edinburgh, Midlothian, Scotland
de Geus, E:
Vrije Univ, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands
Deleuze, JF:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, Commissariat Energie Atom & Energies Alternat, Evry, France
Delgado, GE:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Ekunwe, L:
Univ Mississippi, Jackson Heart Study, Med Ctr, Jackson, MS USA
Faraday, N:
Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Sch Med, Baltimore, MD USA
Gögele, M:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Greinacher, A:
Univ Med Greifswald, Dept Transfus Med, Greifswald, Germany
Gao, H:
Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England
Howard, T:
Univ Texas Rio Grande Valley, Dept Human Genet, Sch Med, Brownsville, TX USA
Joshi, PK:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Kilpeläinen, TO:
Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark
Lahti, J:
Univ Helsinki, Dept Psychol & Logoped, Helsinki, Finland
Linneberg, A:
Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Denmark
Naitza, S:
CNR, Ist Ric Genet & Biomed, Monserrato, Italy
Noordam, R:
Leiden Univ Med Ctr, Dept Internal Medicin, Sect Gerontol & Geriatr, Leiden, Netherlands
Paüls-Vergés, F:
Inst Invest Biomed Sant Pau, Unit Genom Complex Dis, Barcelona, Spain
Rich, SS:
Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA USA
Rosendaal, FR:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Rudan, I:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Ryan, KA:
Univ Maryland, Med, Baltimore, MD USA
Souto, JC:
Inst Recerca Sant Paul, Unit Genom Complex Dis, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis, Madrid, Spain
Hosp Santa Creu & Sant Pau, Unit Thrombosis & Hemostasis, Barcelona, Spain
van Rooij, FJA:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Wang, HM:
Harvard Med Sch, Brigham & Womens Hosp, Med, Boston, MA USA
Zhao, W:
Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI USA
Univ Michigan, Inst Social Res, Res Ctr, Ann Arbor, MI USA
Becker, LC:
Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD USA
Beswick, A:
Univ Bristol, Translat Hlth Sci, Bristol, Avon, England
Cade, BE:
Harvard Med Sch, Brigham & Womens Hosp, Med, Boston, MA USA
Campbell, H:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Cho, K:
Brigham & Womens Hosp, Med, Boston, MA USA
Harvard Med Sch, Boston, MA USA
Crapo, JD:
Natl Jewish Hlth, Denver, CO USA
Curran, JE:
Univ Texas Rio Grande Valley, Dept Human Genet & South Texas Diabet & Obes Inst, Sch Med, Brownsville, TX USA
de Maat, MPM:
Erasmus MC Univ Med Ctr, Dept Hematol, Rotterdam, Netherlands
Doyle, M:
Univ Vermont, Dept Pathol & Lab Med, Larner Coll Med, Colchester, Essex, England
Elliott, P:
Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England
Imperial Coll London, United Kingdom Dementia Res Inst, London, England
Floyd, JS:
Univ Washington, Dept Med, Seattle, WA USA
Univ Washington, Dept Epidemiol, Seattle, WA USA
Fuchsberger, C:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Grarup, N:
Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark
Guo, XQ:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Harris, SE:
Univ Edinburgh, Dept Psychol, Lothian Birth Cohorts, Edinburgh, Midlothian, Scotland
Hou, LF:
Northwestern Univ, Dept Prevent Med, Chicago, IL USA
Kolcic, I:
Univ Split, Fac Med, Split, Croatia
Kooperberg, C:
Fred Hutchinson Canc Ctr, Div Publ Hlth Sci, Seattle, WA USA
Menni, C:
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Nauck, M:
German Ctr Cardiovasc Res, Partner Site Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany
Univ Med Greifswald, Greifswald, Germany
O'Connell, JR:
Univ Maryland, Med, Baltimore, MD USA
Orrú, V:
CNR, Ist Ric Genet & Biomed, Lanusei, Italy
Psaty, BM:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Univ Washington, Dept Epidemiol, Seattle, WA USA
Univ Washington, Dept Hlth Syst & Populat Hlth, Seattle, WA USA
Räikkönen, K:
Univ Helsinki, Dept Psychol & Logoped, Helsinki, Finland
Smith, JA:
Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI USA
Univ Michigan, Inst Social Res, Res Ctr, Ann Arbor, MI USA
Soria, JM:
Inst Recerca Sant Paul, Unit Genom Complex Dis, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis, Madrid, Spain
Stott, DJ:
Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland
Vlieg, AV:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Watkins, H:
Univ Oxford, Dept Med, Oxford, England
Willemsen, G:
Vrije Univ, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands
Wilson, PWF:
VA Atlanta Healthcare Syst, Decatur, GA USA
Emory Univ, Div Cardiol, Sch Med, Atlanta, GA USA
Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA
Ben-Shlomo, Y:
Univ Bristol, Populat Hlth Sci, Bristol, Avon, England
Boomsma, D:
Vrije Univ, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands
Cox, SR:
Univ Edinburgh, Dept Psychol, Lothian Birth Cohorts, Edinburgh, Midlothian, Scotland
Dehghan, A:
Inst Recerca Sant Paul, Unit Genom Complex Dis, Barcelona, Spain
Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England
Imperial Coll London, Sch Publ Hlth, Med Res Council Publ Hlth England Ctr Environm &, London, England
Imperial Coll London, United Kingdom Dementia Res Inst, London, England
Eriksson, JG:
Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland
Folkhalsan Res Ctr, Helsinki, Finland
Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynecol, Singapore, Singapore
Fiorillo, E:
CNR, Ist Ric Genet & Biomed, Lanusei, Italy
Fornage, M:
Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Brown Fdn, Inst Mol Med, Houston, TX USA
Hansen, T:
Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark
Hayward, C:
Univ Edinburgh, Inst Genet & Canc, Med Res Council, Human Genet Unit, Edinburgh, Midlothian, Scotland
Ikram, MA:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Jukema, JW:
Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands
Netherlands Heart Inst, Utrecht, Netherlands
Kardia, SLR:
Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI USA
Lange, LA:
Univ Colorado, Dept Med, Div Biomed Informat & Personalized Med, Anschutz Med Campus, Aurora, CO USA
März, W:
Heidelberg Univ, Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Mannheim, Germany
Mathias, RA:
Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD USA
Mitchell, BD:
Univ Maryland, Med, Baltimore, MD USA
Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA
Mook-Kanamori, DO:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Leiden Univ, Dept Publ Hlth & Primary Care, Med Ctr, Leiden, Netherlands
Morange, PE:
Aix Marseille Univ, Inst Natl Rech Agr, Ctr Rech Cardio Vasc & Nutr, INSERM, Marseille, France
La Timone Hosp, Lab Haematol, Marseille, France
Pedersen, O:
Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark
Pramstaller, PP:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Redline, S:
Harvard Med Sch, Brigham & Womens Hosp, Med, Boston, MA USA
Beth Israel Deaconness Med Ctr, Dept Med, Boston, MA USA
Reiner, A:
Fred Hutchinson Canc Ctr, Div Publ Hlth Sci, Seattle, WA USA
Ridker, PM:
Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA
Silverman, EK:
Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA
Harvard Med Sch, Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA USA
Spector, TD:
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Völker, U:
Univ Med Greifswald, Dept Funct Genom, German Ctr Cardiovasc Res, Partner Site Greifswald,Interfac Inst Genet & Fun, Greifswald, Germany
Wareham, NJ:
Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England
Wilson, JF:
Univ Edinburgh, Inst Genet & Canc, Med Res Council, Human Genet Unit, Edinburgh, Midlothian, Scotland
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland
Yao, J:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Trégouët, DA:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Johnson, AD:
Natl Heart Lung & Blood Inst, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Wolberg, AS:
Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC USA
Univ North Carolina Chapel Hill, UNC Blood Res Ctr, Chapel Hill, NC USA
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol, Ctr Human Genet, Houston, TX USA
Sabater-Lleal, M:
Inst Recerca Sant Paul, Unit Genom Complex Dis, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis, Madrid, Spain
Karolinska Inst, Dept Med, Cardiovasc Med Unit, Ctr Mol Med, Stockholm, Sweden
Morrison, AC:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol, Ctr Human Genet, Houston, TX USA
Smith, NL:
Univ Washington, Dept Epidemiol, Seattle, WA USA
Kaiser Permanente Washington, Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA
Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA
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