Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
Bibliographical noteFunding Information:
Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung and Blood Institute grant R01HL105756. ARIC is carried out as a collaborative study supported by National Heart, Lung and Blood Institute (NHLBI) contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402 and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. B58C acknowledges use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research. BMES has been supported by the Australian National Health & Medical Research Council, Canberra Australia (grant numbers 974159, 211069, 457349, 512423, 475604, 529912 and the funding for Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, CCRE in TCR-Eye, grant ID 529923); in addition, funding by the Wellcome Trust, UK (to A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis and P. Foster) has supported the genotyping costs of the entire BMES population. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The CROATIA-Split study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (contract no. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract no. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). The EPIC Norfolk Study is funded by program grants from the Medical Research Council UK and Cancer Research UK, and by additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and the Wellcome Trust. FHS was partially supported by the National Heart, Lung, and Blood Institute''s (NHLBI''s) Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Partial investigator support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases K24 DK080140 (J.B. Meigs), the National Institute on Aging and National Institute for Neurological Disorders and Stroke R01 AG033193, NS017950 (S Seshadri). GeneSTAR was supported by grants from the National Institutes of Health/National Heart, Lung and Blood Institute (U01 HL72518, HL097698, HL59684 and HL071025-01A1), the National Institutes of Health/National Institute of Nursing Research (NR0224103) and the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. The Genetic Epidemiology Network of Arteriopathy (GENOA) study is supported by the National Institutes of Health, grant numbers HL087660 and HL100245 from National Heart, Lung, Blood Institute. Tarunveer Singh Ahluwalia received his post-doctoral research funding from GENDINOB project and acknowledges the same. The Gutenberg Health Study is funded through the government of Rhineland-Palatinate (''Stiftung Rheinland-Pfalz f?r Innovation'', contract AZ 961-386261/733), the research programs ''Wissen schafft Zukunft'' and ''Center for Translational Vascular Biology (CTVB)'' of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. V.G. and P.S.W. are funded by the Federal Ministry of Education and Research (BMBF 01EO1003). Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkh?lsan Research Foundation, Novo Nordisk Foundation, Finska L?kares?llskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. The InCHIANTI study baseline (1998-2000) was supported as a ''targeted project'' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts:263 MD 9164 and 263 MD 821336); this researchwas supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The KORA studies were financed by the Helmholtz Zentrum M?nchen, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF) and by the state of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of LMU innovative. The whole genome association study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; Ref. BB/F019394/1). The LBC1936 research was supported by Age UK. The LBC1921 data collection was funded by the BBSRC. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the Biotechnology and Biological Sciences Research Council (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and Medical Research Council (MRC) is gratefully acknowledged. LURIC has received funding from the sixth Framework Program (integrated project Bloodomics, grant no.: LSHM-CT-2004-503485) and from the seventh Framework Program (Atheroremo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union as well as from the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and theWissenschaftsoffensive TMO. The MARTHA project was supported by grants from the Program Hospitalier de Recherche Clinique. Statistical analyses of the MARTHA dataset were performed using the C2BIG computing cluster, funded by the R?gion Ile de France, Pierre and Marie Curie University, and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05). MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. NTR: funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, addiction-31160008, middelgroot-911-09-032, Spinozapremie 56-464-14192, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007). VU University''s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community''s Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC Advanced, 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951). Part of the genotyping and analyseswere funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computingwas supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation, the Wellcome Trust (contract no. 075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar S?derberg Foundation, the Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council. Jemma C. Hopewell and Robert Clarke acknowledge support from the BHF Centre of Research Excellence, Oxford. M.Sabater-Lleal is supported by the Swedish Heart-Lung Foundation (20130399), and acknowledges funding from ?ke Wiberg and Tore Nilssons foundations. B.Sennblad acknowledges funding from the Magnus Bergvall Foundation and the Foundation for Old Servants. PROSPER-PHASE received funding from the European Union''s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F2-2009-223004. For a part of the genotyping we received funding from the Netherlands Consortium of Healthy Aging (NGI:05060810). Measurement of serum fibrinogen was supported by a grant from the Scottish Executive Chief Scientist Office, Health Services Research Committee grant number CZG/4/306. This work was performed as part of an ongoing collaboration of the PROSPER study group in the universities of Leiden, Glasgow and Cork. Professor Dr J.W. J. is an Established Clinical Investigator of the Netherlands Heart Foundation (2001D 032). The generation and management ofGWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project no. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. A.D. is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. The SardiNIA (''ProgeNIA'') teamwas supported by contract NO1-AG-1-2109 from the NIA. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, by Sardinian Autonomous Region (L.R. no. 7/2009) grant cRP3-154, and by grant FaReBio2011 ''Farmaci e Reti Biotecnologiche di Qualit?''. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. Computing resources have been made available by the Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB project h1231). The University of Greifswald is a member of the ''Center of Knowledge Interchange'' program of the Siemens AG and the Cach? Campus program of the InterSystems GmbH. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania (03IS2061A). TwinsUK was funded by the Wellcome Trust; European Community''s Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy''s & St Thomas'' NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy''s and St Thomas'' NHS Foundation Trust and King''s College London. Tim Spector is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung and Blood Institute and CA047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The WHI program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN2712011 00004C. Genotyping and analysis were supported through the Women''s Health Initiative Sequencing Project (NHLBI RC2 HL-102924), the Genetics and Epidemiology of Colorectal Cancer Consortium (NCI CA137088), the Genomics and Randomized Trials Network (NHGRI U01-HG005152), and an NCI training grant (R25CA094880).