Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease
Authors: Sabater-Lleal Maria , Huang Jie , Chasman Daniel , Naitza Silvia , Dehghan Abbas , Johnson Andrew D. , Teumer Alexander , Reiner Alex P. , Folkersen Lasse , Basu Saonli , Rudnicka Alicja R. , Trompet Stella , Mälarstig Anders , Baumert Jens , Bis Joshua C. , Guo Xiuqing , Hottenga Jouke J. , Shin So-Youn , Lopez Lorna M. , Lahti Jari , Tanaka Toshiko , Yanek Lisa R. , Oudot-Mellakh Tiphaine , Wilson James F. , Navarro Pau , Huffman Jennifer E. , Zemunik Tatijana , Redline Susan , Mehra Reena , Pulanic Drazen , Rudan Igor , Wright Alan F. , Kolcic Ivana , Polasek Ozren , Wild Sarah H. , Campbell Harry , Curb J. David , Wallace Robert , Liu Simin , Eaton Charles B. , Becker Diane M. , Becker Lewis C. , Bandinelli Stefania , Räikkönen Katri , Widen Elisabeth , Palotie Aarno , Fornage Myriam , Green David , Gross Myron , Davies Gail , Harris Sarah E. , Liewald David C. , Starr John M. , Williams Frances M.K. , Grant Peter J. , Spector Timothy D. , Strawbridge Rona J. , Silveira Angela , Sennblad Bengt , Rivadeneira Fernando , Uitterlinden Andre G. , Franco Oscar H. , Hofman Albert , van Dongen Jenny , Willemsen Gonneke , Boomsma Dorret I. , Yao Jie , Swords Jenny Nancy , Haritunians Talin , McKnight Barbara , Lumley Thomas , Taylor Kent D. , Rotter Jerome I. , Psaty Bruce M. , Peters Annette , Gieger Christian , Illig Thomas , Grotevendt Anne , Homuth Georg , Völzke Henry , Kocher Thomas , Goel Anuj , Franzosi Maria Grazia , Seedorf Udo , Clarke Robert , Steri Maristella , Tarasov Kirill V. , Sanna Serena , Schlessinger David , Stott David J. , Sattar Naveed , Buckley Brendan M. , Rumley Ann , Lowe Gordon D. , McArdle Wendy L. , Chen Ming-Huei , Tofler Geoffrey H. , Song Jaejoon , Boerwinkle Eric , Folsom Aaron R. , Rose Lynda M. , Franco-Cereceda Anders , Teichert Martina , Ikram M. Arfan , Mosley Thomas H. , Bevan Steve , Dichgans Martin , Rothwell Peter M. , Sudlow Cathie L.M. , Hopewell Jemma C. , Chambers John C. , Saleheen Danish , Kooner Jaspal S. , Danesh John , Nelson Christopher P. , Erdmann Jeanette , Reilly Muredach P. , Kathiresan Sekar , Schunkert Heribert , Morange Pierre-Emmanuel , Ferrucci Luigi , Eriksson Johan G. , Jacobs David , Deary Ian J. , Soranzo Nicole , Witteman Jacqueline C.M. , de Geus Eco J.C. , Tracy Russell P. , Hayward Caroline , Koenig Wolfgang , Cucca Francesco , Jukema J. Wouter , Eriksson Per , Seshadri Sudha , Markus Hugh S. , Watkins Hugh , Samani Nilesh J. , Wallaschofski Henri , Smith Nicholas L. , Tregouet David , Ridker Paul M , Tang Weihong , Strachan David P. , Hamsten Anders , O’Donnell Christopher J. 
Published: August 2013

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 and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (
P
<5×10
−8
) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

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.