Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
Por:
Thibord, F, Klarin, D, Brody, JA, Chen, MH, Levin, MG, Chasman, DI, Goode, EL, Hveem, K, Teder-Laving, M, Martinez-Perez, A, Aissi, D, Daian-Bacq, D, Ito, K, Natarajan, P, Lutsey, PL, Nadkarni, GN, de Vries, PS, Cuellar-Partida, G, Wolford, BN, Pattee, JW, Kooperberg, C, Braekkan, SK, Li-Gao, RF, Saut, N, Sept, C, Germain, M, Judy, RL, Wiggins, KL, Ko, D, O'Donnell, CJ, Taylor, KD, Giulianini, F, De Andrade, M, Nost, TH, Boland, A, Empana, JP, Koyama, S, Gilliland, T, Do, R, Huffman, JE, Wang, X, Zhou, W, Soria, JM, Souto, JC, Pankratz, N, Haessler, J, Hindberg, K, Rosendaal, FR, Turman, C, Olaso, R, Kember, RL, Bartz, TM, Lynch, JA, Heckbert, SR, Armasu, SM, Brumpton, B, Smadja, DM, Jouven, X, Komuro, I, Clapham, KR, Loos, RJF, Willer, CJ, Sabater-Lleal, M, Pankow, JS, Reiner, AP, Morelli, VM, Ridker, PM, Vlieg, AV, Deleuze, JF, Kraft, P, Rader, DJ, Lee, KM, Psaty, BM, Skogholt, AH, Emmerich, J, Suchon, P, Rich, SS, Vy, HT, Tang, WH, Jackson, RD, Hansen, JB, Morange, PE, Kabrhel, C, Tregouet, DA, Damrauer, SM, Johnson, AD, Smith, NL
Publicada:
18 oct 2022
Resumen:
Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
Filiaciones:
Thibord, F:
Natl Heart Lung & Blood Inst, Populat Sci Branch, Div Intramural Res, Framingham, MA USA
Boston Univ, Framingham Heart Study, Framingham, MA USA
Klarin, D:
Stanford Univ, Sch Med, Div Vasc Surg, Stanford, CA 94305 USA
Vet Affairs Palo Alto Healthcare Syst, Palo Alto, CA USA
Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA
Brody, JA:
Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA
Chen, MH:
Natl Heart Lung & Blood Inst, Populat Sci Branch, Div Intramural Res, Framingham, MA USA
Boston Univ, Framingham Heart Study, Framingham, MA USA
Levin, MG:
Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA
Chasman, DI:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Boston, MA 02115 USA
Goode, EL:
Mayo Clin, Dept Quantitat Hlth Sci, Rochester, MN USA
Hveem, K:
Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, HUNT Res Ctr, Levanger, Norway
Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Teder-Laving, M:
Univ Tartu, Inst Genom, Tartu, Estonia
Martinez-Perez, A:
Inst Invest Biomed St Pau, Genom Complex Dis Unit, Barcelona, Spain
Aissi, D:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Inst Natl Sante & Rech Med, UMR1219, Bordeaux, France
Daian-Bacq, D:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, France
GenMed, Lab Excellence Med Genom, Paris, France
Ito, K:
RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Genom & Informat, Yokohama, Kanagawa, Japan
Natarajan, P:
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA
Broad Inst Harvard & Massachusetts Inst Technol, Cardiovasc Dis Initiat, Cambridge, MA USA
Lutsey, PL:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Nadkarni, GN:
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Houston, TX 77030 USA
Cuellar-Partida, G:
23andMe Inc, Sunnyvale, CA USA
Wolford, BN:
Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
Pattee, JW:
Univ Minnesota, Div Biostat, Minneapolis, MN USA
Colorado Sch Publ Hlth, Ctr Innovat Design & Anal, Aurora, CO USA
Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA
Kooperberg, C:
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA
Braekkan, SK:
UiT Arctic Univ Norway, Thrombosis Res Ctr, Tromso, Norway
Univ Hosp North Norway, Div Internal Med, Tromso, Norway
Li-Gao, RF:
Leiden Univ Med Ctr, Clin Epidemiol, Leiden, Netherlands
Saut, N:
La Timone Univ Hosp Marseille, Hematol Lab, Marseille, France
Aix Marseille Univ, C2VN, Inst Natl Sante & Rech Med, Inst Natl Rech Agr Alimentat & Environm, Marseille, France
Sept, C:
Harvard TH Chan Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA
Germain, M:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Inst Natl Sante & Rech Med, UMR1219, Bordeaux, France
GenMed, Lab Excellence Med Genom, Paris, France
Judy, RL:
Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA
Wiggins, KL:
Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA
Ko, D:
Boston Univ, Framingham Heart Study, Framingham, MA USA
O'Donnell, CJ:
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Vet Affairs Boston Healthcare Syst, Cardiol Sect, Dept Med, Boston, MA USA
Taylor, KD:
Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Torrance, CA USA
Giulianini, F:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
De Andrade, M:
Mayo Clin, Dept Quantitat Hlth Sci, Rochester, MN USA
Nost, TH:
Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Boland, A:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, France
GenMed, Lab Excellence Med Genom, Paris, France
Empana, JP:
Univ Paris Cite, Paris Cardiovasc Res Ctr, Integrat Epidemiol Cardiovasc Dis, Paris, France
Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Cardiol, Paris, France
Koyama, S:
RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Genom & Informat, Yokohama, Kanagawa, Japan
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA
Broad Inst Harvard & Massachusetts Inst Technol, Cardiovasc Dis Initiat, Cambridge, MA USA
Gilliland, T:
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA
Broad Inst Harvard & Massachusetts Inst Technol, Cardiovasc Dis Initiat, Cambridge, MA USA
Do, R:
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, BioMe Phen Ctr, New York, NY 10029 USA
Huffman, JE:
Vet Affairs Boston Healthcare Syst, MAVERIC, Boston, MA USA
Wang, X:
23andMe Inc, Sunnyvale, CA USA
Zhou, W:
Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Soria, JM:
Inst Invest Biomed St Pau, Genom Complex Dis Unit, Barcelona, Spain
Souto, JC:
Inst Invest Biomed St Pau, Genom Complex Dis Unit, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Unit Thrombosis & Hemostasis, Barcelona, Spain
Pankratz, N:
Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN USA
Haessler, J:
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA
Hindberg, K:
UiT Arctic Univ Norway, Thrombosis Res Ctr, Tromso, Norway
Rosendaal, FR:
Leiden Univ Med Ctr, Clin Epidemiol, Leiden, Netherlands
Turman, C:
Harvard TH Chan Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA
Olaso, R:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, France
GenMed, Lab Excellence Med Genom, Paris, France
Kember, RL:
Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA
Bartz, TM:
Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA USA
Univ Washington, Dept Med, Seattle, WA USA
Lynch, JA:
Vet Affairs Salt Lake City Healthcare Syst, Vet Affairs Informat & Comp Infrastruct, Salt Lake City, UT USA
Univ Utah, Epidemiol, Salt Lake City, UT USA
Heckbert, SR:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Armasu, SM:
Mayo Clin, Dept Quantitat Hlth Sci, Rochester, MN USA
Brumpton, B:
Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Smadja, DM:
Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Paris, France
Univ Paris, Inst Natl Sante & Rech Med DMS, Innovat Therapies Haemostasis, Paris, France
Jouven, X:
Univ Paris 05, Integrat Epidemiol Cardiovasc Dis, Sorbonne Paris Cite, Paris, France
Univ Paris 05, Sorbonne Paris Cite, Inst Natl Sante & Rech Med, Inserm U970,Paris Cardiovasc Res Ctr, Paris, France
Komuro, I:
Univ Tokyo, Dept Cardiovasc Med, Tokyo, Japan
Clapham, KR:
Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA
Broad Inst Harvard & Massachusetts Inst Technol, Cardiovasc Dis Initiat, Cambridge, MA USA
Loos, RJF:
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA
Willer, CJ:
Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
Sabater-Lleal, M:
Inst Invest Biomed St Pau, Genom Complex Dis Unit, Barcelona, Spain
Karolinska Inst, Cardiovasc Med Unit, Dept Med, Ctr Mol Med, Stockholm, Sweden
Pankow, JS:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Reiner, AP:
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Morelli, VM:
UiT Arctic Univ Norway, Thrombosis Res Ctr, Tromso, Norway
Univ Hosp North Norway, Div Internal Med, Tromso, Norway
Ridker, PM:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Boston, MA 02115 USA
Vlieg, AV:
Leiden Univ Med Ctr, Clin Epidemiol, Leiden, Netherlands
Deleuze, JF:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, France
GenMed, Lab Excellence Med Genom, Paris, France
Fdn Jean Daussel, Ctr Etud Polymorphisme Humain, Paris, France
Kraft, P:
Harvard TH Chan Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA
Rader, DJ:
Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA
Lee, KM:
Vet Affairs Salt Lake City Healthcare Syst, Vet Affairs Informat & Comp Infrastruct, Salt Lake City, UT USA
Psaty, BM:
Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA
Univ Washington, Dept Hlth Syst & Populat Heath, Seattle, WA 98195 USA
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Skogholt, AH:
Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Emmerich, J:
Univ Paris, Dept Vasc Med, Paris St Joseph Hosp Grp, Paris, France
Inst Natl Sante & Rech Med CRESS, UMR1153, Paris, France
Suchon, P:
La Timone Univ Hosp Marseille, Hematol Lab, Marseille, France
Rich, SS:
Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA
Vy, HT:
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
Tang, WH:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Jackson, RD:
Ohio State Univ, Coll Med, Columbus, OH USA
Hansen, JB:
UiT Arctic Univ Norway, Thrombosis Res Ctr, Tromso, Norway
Univ Hosp North Norway, Div Internal Med, Tromso, Norway
Morange, PE:
La Timone Univ Hosp Marseille, Hematol Lab, Marseille, France
Aix Marseille Univ, C2VN, Inst Natl Sante & Rech Med, Inst Natl Rech Agr Alimentat & Environm, Marseille, France
Kabrhel, C:
Harvard Med Sch, Emergency Med, Boston, MA 02115 USA
Massachusetts Gen Hosp, Emergency Med, Boston, MA 02114 USA
Tregouet, DA:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Inst Natl Sante & Rech Med, UMR1219, Bordeaux, France
GenMed, Lab Excellence Med Genom, Paris, France
Damrauer, SM:
Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA
Corporal Michael J Crescenz Philadelphia Vet Affa, Philadelphia, PA USA
Johnson, AD:
Natl Heart Lung & Blood Inst, Populat Sci Branch, Div Intramural Res, Framingham, MA USA
Boston Univ, Framingham Heart Study, Framingham, MA USA
Smith, NL:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Kaiser Permanents Washington Hlth Res Inst, Seattle, WA USA
Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA
Green Submitted, All Open Access; Green
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