This article is part of the supplement: The Framingham Heart Study 100,000 single nucleotide polymorphisms resource

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Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study

Qiong Yang12, Sekar Kathiresan136, Jing-Ping Lin4, Geoffrey H Tofler5 and Christopher J O'Donnell16*

Author Affiliations

1 The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA

2 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

3 Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA

4 Office of Biostatistics Research, NHLBI, National Institute of Health; Bethesda, MD, USA

5 Royal North Shore Hospital Sydney, Australia

6 Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

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BMC Medical Genetics 2007, 8(Suppl 1):S12  doi:10.1186/1471-2350-8-S1-S12

Published: 19 September 2007



Increased circulating levels of hemostatic factors as well as anemia have been associated with increased risk of cardiovascular disease (CVD). Known associations between hemostatic factors and sequence variants at genes encoding these factors explain only a small proportion of total phenotypic variation. We sought to confirm known putative loci and identify novel loci that may influence either trait in genome-wide association and linkage analyses using the Affymetrix GeneChip 100K single nucleotide polymorphism (SNP) set.


Plasma levels of circulating hemostatic factors (fibrinogen, factor VII, plasminogen activator inhibitor-1, von Willebrand factor, tissue plasminogen activator, D-dimer) and hematological phenotypes (platelet aggregation, viscosity, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin concentration) were obtained in approximately 1000 Framingham Heart Study (FHS) participants from 310 families. Population-based association analyses using the generalized estimating equations (GEE), family-based association test (FBAT), and multipoint variance components linkage analyses were performed on the multivariable adjusted residuals of hemostatic and hematological phenotypes.


In association analysis, the lowest GEE p-value for hemostatic factors was p = 4.5*10-16 for factor VII at SNP rs561241, a variant located near the F7 gene and in complete linkage disequilibrium (LD) (r2 = 1) with the Arg353Gln F7 SNP previously shown to account for 9% of total phenotypic variance. The lowest GEE p-value for hematological phenotypes was 7*10-8 at SNP rs2412522 on chromosome 4 for mean corpuscular hemoglobin concentration. We presented top 25 most significant GEE results with p-values in the range of 10-6 to 10-5 for hemostatic or hematological phenotypes. In relating 100K SNPs to known candidate genes, we identified two SNPs (rs1582055, rs4897475) in erythrocyte membrane protein band 4.1-like 2 (EPB41L2) associated with hematological phenotypes (GEE p < 10-3). In linkage analyses, the highest linkage LOD score for hemostatic factors was 3.3 for factor VII on chromosome 10 around 15 Mb, and for hematological phenotypes, LOD 3.4 for hemoglobin on chromosome 4 around 55 Mb. All GEE and FBAT association and variance components linkage results can be found at webcite


Using genome-wide association methodology, we have successfully identified a SNP in complete LD with a sequence variant previously shown to be strongly associated with factor VII, providing proof of principle for this approach. Further study of additional strongly associated SNPs and linked regions may identify novel variants that influence the inter-individual variability in hemostatic factors and hematological phenotypes.