Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

M Sabater-Lleal, J Huang, D Chasman, S Naitza, Abbas Dehghan, AD Johnson, A Teumer, AP Reiner, L Folkersen, Sreya Basu, AR Rudnicka, S Trompet, A Malarstig, J Baumert, JC Bis, XQ Guo, JJ (Jouke Jan) Hottenga, SY Shin, LM Lopez, J LahtiT Tanaka, LR Yanek, T Oudot-Mellakh, JF Wilson, P Navarro, JE Huffman, T Zemunik, S Redline, R Mehra, D Pulanic, I Rudan, AF Wright, I Kolcic, O Polasek, SH Wild, H Campbell, JD Curb, R Wallace, SM (Simin) Liu, CB Eaton, DM Becker, LC Becker, S Bandinelli, K Raikkonen, E Widen, A Palotie, M Fornage, D Green, M Gross, G Davies, SE Harris, DC Liewald, JM Starr, FMK Williams, PJ Grant, TD Spector, RJ Strawbridge, A Silveira, B Sennblad, Fernando Rivadeneira, André Uitterlinden, OH Franco Duran, Bert Hofman, Jacques Dongen, G Willemsen, DI Boomsma, JJ Yao, NS Jenny, T Haritunians, B McKnight, T Lumley, KD Taylor, JI Rotter, BM Psaty, A Peters, C Gieger, T Illig, A Grotevendt, G Homuth, H Volzke, T Kocher, A Goel, MG Franzosi, U Seedorf, R Clarke, M Steri, KV Tarasov, S Sanna, D Schlessinger, DJ Stott, N Sattar, BM Buckley, A Rumley, GD Lowe, WL McArdle, MH Chen, GH Tofler, J Song, E Boerwinkle, AR Folsom, LM Rose, A Franco-Cereceda, Martina Teichert, Arfan Ikram, TH Mosley, S Bevan, M Dichgans, PM Rothwell, CLM Sudlow, JC Hopewell, JC Chambers, D Saleheen, JS Kooner, J Danesh, CP Nelson, J Erdmann, MP Reilly, S Kathiresan, H Schunkert, PE Morange, L Ferrucci, JG Eriksson, D Jacobs, IJ Deary, N Soranzo, JCM Witteman, EJC de Geus, RP Tracy, C Hayward, W Koenig, F Cucca, JW Jukema, P Eriksson, S Seshadri, HS Markus, H Watkins, NJ Samani, H Wallaschofski, NL Smith, D Tregouet, PM Ridker, WH Tang, DP Strachan, A Hamsten, CJ O'Donnell

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Abstract

Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases Conclusions We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
Original languageUndefined/Unknown
Pages (from-to)1310-1324
Number of pages15
JournalCirculation
Volume128
Issue number12
DOIs
Publication statusPublished - 2013

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