Background-Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. Methods and Results-We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, ). These included a single-nucleotide polymorphism located in the fibrinogen  chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (Pϭ1.8ϫ10
Clinical Perspective see p 133The objective of this study was to identify novel genetic loci related to plasma fibrinogen levels. A meta-analysis of genome-wide association (GWA) findings was conducted on 6 population-based studies. We analyzed GWA data of 2 661 766 single-nucleotide polymorphisms (SNPs) from 1 or more studies from a total of 22 096 participants of European descent.
MethodsThe setting for this meta-analysis is primarily the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. 5
The Rotterdam StudyThe RS is a prospective, population-based cohort study of determinants of several chronic diseases in older adults. 6 In brief, the study comprised 7983 inhabitants of Ommoord, a district of Rotterdam in the Netherlands, who were 55 years or older. The baseline examination took place between 1990 and 1993.Genotyping was conducted using the Illumina 550K array. SNPs were excluded for minor allele frequency (MAF) Յ1%, HardyWeinberg equilibrium (HWE) PϽ10 Ϫ5 , or SNP call rate Յ90%, resulting in data on 530 683 SNPs. Imputation was done with reference to HapMap release 22 CEU using the maximum likelihood method implemented in MACH (http://www.sph.umich.edu/csg/ abecasis/MACH/index.html). The final population for this fibrinogen analysis comprised 2068 individuals.
Framingham Heart StudyThe FHS started in 1948 with 5209 randomly ascertained participants from Framingham, Mass, who had undergone biannual examinations to investigate cardiovascular disease and its risk factors. 7 In 1971, the offspring cohort 8,9 (comprised of 5124 children of the original cohort and the children's spouses) and in 2002, the third generation (consisting of 4095 children of the offspring cohort), were recruited. 10 FHS participants in this study are of European ancestry.Genotyping was carried out as a part of the SNP Health Association Resource project using the Affymetrix 500K mapping array (250K Nsp and 250K Sty arrays) and the Affymetrix 50K supplemental gene focused array on 9274 individuals. Genotyping resulted in 503 551 SNPs with successful call rate Ͼ95% and HWE PϾ10 Ϫ6 on 8481 individuals with call rate Ͼ97%. Imputation of Ϸ2.5 million autosomal SNPs in HapMap with reference to release 22 CEU sample was conducted using the algorithm implemented in MACH. The final population for fibrinogen analysis included 7022 individuals (original cohort, nϭ383; offspri...