Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
Por:
Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AV, de Andrade, M, Brody, JA, Pattee, JW, Haessler, J, Brumpton, B, Chasman, DI, Suchon, P, Chen, MH, Turman, C, Germain, M, Wiggins, KL, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianini, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Damrauer, SM, Natarajan, P, Klarin, D, de Vries, PS, Sabater-Lleal, M, Huffman, JE, Bammler, TK, Frazer, KA, McCauley, BM, Taylor, K, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, JF, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, JB, Rosendaal, FR, Heit, JA, Psaty, BM, Tang, WH, Kooperberg, C, Hveem, K, Ridker, PM, Morange, PE, Johnson, AD, Kabrhel, C, Tregouet, DA, Smith, NL, Busenkell, E, Judy, R, Lynch, J, Levin, M, Aragam, JHK, Chaffin, M, Haas, M, Assimes, TL, Huang, J, Lee, KM, Shao, Q, Kabrhel, C, Huang, YF, Sun, YV, Vujkovic, M, Saleheen, D, Miller, DR, Reaven, P, DuVall, S, Boden, W, Pyarajan, S, Henke, P, Kooperberg, C, Gaziano, JM, Concato, J, Rader, DJ, Cho, K, Chang, KM, Wilson, PWF, Tsao, PS, Kathiresan, S, Obi, A, Million Veteran Program, CHARGE Hemostasis Working Grp, INVENT Consortium
Publicada:
7 nov 2019
Resumen:
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
Filiaciones:
Lindstrom, S:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA
Wang, L:
Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA
Smith, EN:
Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Univ Calif San Diego, Rady Childrens Hosp, La Jolla, CA 92093 USA
UiT Arctic Univ Norway, KG Jebsen Thrombosis Res & Expertise Ctr, Dept Clin Med, Tromso, Norway
Gordon, W:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Vlieg, AV:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
de Andrade, M:
Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Brody, JA:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Pattee, JW:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
Haessler, J:
Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA
Brumpton, B:
Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol, Avon, England
Trondheim Reg & Univ Hosp, St Olavs Hosp, Clin Thorac & Occupat Med, Trondheim, Norway
Chasman, DI:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Suchon, P:
La Timone Hosp, Lab Haematol, Marseille, France
Univ Aix Marseille, Ctr CardioVasc & Nutr Res C2VN, INRA, INSERM, Marseille, France
Chen, MH:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Turman, C:
Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA
Germain, M:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM UMR S 1219, Bordeaux, France
Wiggins, KL:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
MacDonald, J:
Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA
Braekkan, SK:
UiT Arctic Univ Norway, KG Jebsen Thrombosis Res & Expertise Ctr, Dept Clin Med, Tromso, Norway
Univ Hosp North Norway, Div Internal Med, Tromso, Norway
Armasu, SM:
Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Pankratz, N:
Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
Jackson, RD:
Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA
Nielsen, JB:
Univ Michigan, Dept Internal Med, Div Cardiol, Med Sch, Ann Arbor, MI 48109 USA
Giulianini, F:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Puurunen, MK:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Ibrahim, M:
La Timone Hosp, Lab Haematol, Marseille, France
Heckbert, SR:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Kaiser Permanente Washington, Hlth Res Inst, Seattle, WA USA
Damrauer, SM:
Corporal Michael Crescenz VA Med Ctr, Dept Surg, Philadelphia, PA USA
Univ Penn, Dept Surg, Perleman Sch Med, Philadelphia, PA 19104 USA
Natarajan, P:
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Boston VA Healthcare Syst, Boston, MA USA
Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA
Klarin, D:
Boston VA Healthcare Syst, Boston, MA USA
Harvard Med Sch, Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02115 USA
Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA
Sabater-Lleal, M:
IIB St Pau, Inst Recerca Hosp St Pau, Unit Genom Complex Dis, Barcelona, Spain
Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med, Cardiovasc Med Unit,Dept Med, Stockholm, Sweden
Huffman, JE:
VA Boston Healthcare Syst, MAVERIC, Ctr Populat Genom, Boston, MA USA
Bammler, TK:
Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA
Frazer, KA:
Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Univ Calif San Diego, Rady Childrens Hosp, La Jolla, CA 92093 USA
UiT Arctic Univ Norway, KG Jebsen Thrombosis Res & Expertise Ctr, Dept Clin Med, Tromso, Norway
Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
McCauley, BM:
Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Taylor, K:
Harbor Univ Calif Los Angeles Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA USA
Harbor Univ Calif Los Angeles Med Ctr, Dept Pediat, Torrance, CA USA
Pankow, JS:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Reiner, AP:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA
Gabrielsen, ME:
Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Deleuze, JF:
Commissariat Energie Atom & Energies Alternat, Ctr Natl Rech Genom Humaine, Direct Rech Fondamentale, Evry, France
Fdn Jean Dausset, CEPH, Paris, France
O'Donnell, CJ:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Vet Adm, Mill Vet Program, Boston, MA USA
Kim, J:
Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA
McKnight, B:
Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA
Univ Washington, Dept Biostat, Seattle, WA 98195 USA
Kraft, P:
Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA
Hansen, JB:
UiT Arctic Univ Norway, KG Jebsen Thrombosis Res & Expertise Ctr, Dept Clin Med, Tromso, Norway
Univ Hosp North Norway, Div Internal Med, Tromso, Norway
Rosendaal, FR:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
Heit, JA:
Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Psaty, BM:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Kaiser Permanente Washington, Hlth Res Inst, Seattle, WA USA
Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA
Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA
Tang, WH:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Kooperberg, C:
Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA
Hveem, K:
Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Ridker, PM:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Dept Med, Boston, MA 02115 USA
Morange, PE:
La Timone Hosp, Lab Haematol, Marseille, France
Univ Aix Marseille, Ctr CardioVasc & Nutr Res C2VN, INRA, INSERM, Marseille, France
AP HM, HemoVasc, Ctr Ressources Biol, Marseille, France
Johnson, AD:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Kabrhel, C:
Massachusetts Gen Hosp, Dept Emergency Med, Ctr Vasc Emergencies, Boston, MA 02114 USA
Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Dept Emergency Med, Boston, MA 02115 USA
Tregouet, DA:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM UMR S 1219, Bordeaux, France
Smith, NL:
Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
Kaiser Permanente Washington, Hlth Res Inst, Seattle, WA USA
Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA
Kabrhel, C:
Massachusetts Gen Hosp, Dept Emergency Med, Ctr Vasc Emergencies, Boston, MA 02114 USA
Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Dept Emergency Med, Boston, MA 02115 USA
Kooperberg, C:
Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, 1124 Columbia St, Seattle, WA 98104 USA
Green Published, Bronze
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