A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium

Weihong Tang^#¹, Martina Teichert^#^{2

3}, Daniel I Chasman^#^{4

5}, John A Heit^#⁶, Pierre-Emmanuel Morange^#⁷, Guo Li^#⁸, Nathan Pankratz⁹, Frank W Leebeek¹⁰, Guillaume Paré¹¹, Mariza de Andrade¹², Christophe Tzourio¹³, Bruce M Psaty^{14

15}, Saonli Basu¹⁶, Rikje Ruiter², Lynda Rose⁴, Sebastian M Armasu¹², Thomas Lumley¹⁷, Susan R Heckbert^{18

15

19}, André G Uitterlinden^{2

20

21}, Mark Lathrop²², Kenneth M Rice²³, Mary Cushman²⁴, Albert Hofman², Jean-Charles Lambert²⁵, Nicole L Glazer²⁶, James S Pankow¹, Jacqueline C Witteman², Philippe Amouyel^{25

27}, Joshua C Bis⁸, Edwin G Bovill²⁸, Xiaoxiao Kong¹⁶, Russell P Tracy²⁹, Eric Boerwinkle³⁰, Jerome I Rotter³¹, David-Alexandre Trégouët³², Daan W Loth^{2

33}, Bruno H Ch Stricker^#^{2

21

33}, Paul M Ridker^#^{4

5}, Aaron R Folsom^#¹, Nicholas L Smith^#^{18

19}

Affiliations

¹ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Scientific Institute Dutch Pharmacists, The Hague, The Netherlands.
⁴ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Harvard Medical School, Boston, MA, USA.
⁶ Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ INSERM UMR_S 1062; Université de la Méditerranée, Marseille, France.
⁸ Department of Medicine, University of Washington, Seattle, WA, USA.
⁹ Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
¹⁰ Department of Haematology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹¹ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, L8S4K1, Canada.
¹² Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
¹³ University of Bordeaux, U708, F-33000, Bordeaux, France.
¹⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
¹⁵ Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
¹⁶ Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Department of Statistics, University of Aukland, Aukland, NZ.
¹⁸ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁹ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
²⁰ Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.
²¹ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
²² Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, F-91057, Evry, France.
²³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁴ Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont, USA.
²⁵ INSERM, UMR_S 744, Institut Pasteur de Lille; Université de Lille Nord de France, F-59019, Lille, France.
²⁶ Department of Medicine, Boston University, Boston, MA, USA.
²⁷ Centre Hospitalier Régional Universitaire de Lille, F-59037, Lille, France.
²⁸ Department of Pathology, University of Vermont, Burlington, VT, USA.
²⁹ Departments of Biochemistry and Pathology, University of Vermont, Burlington, VT, USA.
³⁰ Human Genetics Center and Human Genome Sequencing Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
³¹ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² INSERM, UMR_S 937, ICAN Institute for Cardiometabolism and Nutrition, University Pierre & Marie Curie, Paris 06, F-75013, Paris, France.
³³ Drug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands.

^# Contributed equally.

PMID: 23650146
PMCID: PMC3990406
DOI: 10.1002/gepi.21731

A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium

Weihong Tang et al. Genet Epidemiol. 2013 Jul.

. 2013 Jul;37(5):512-521.

doi: 10.1002/gepi.21731. Epub 2013 May 5.

Authors

Affiliations

¹ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Scientific Institute Dutch Pharmacists, The Hague, The Netherlands.
⁴ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Harvard Medical School, Boston, MA, USA.
⁶ Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ INSERM UMR_S 1062; Université de la Méditerranée, Marseille, France.
⁸ Department of Medicine, University of Washington, Seattle, WA, USA.
⁹ Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
¹⁰ Department of Haematology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹¹ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, L8S4K1, Canada.
¹² Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
¹³ University of Bordeaux, U708, F-33000, Bordeaux, France.
¹⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
¹⁵ Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
¹⁶ Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Department of Statistics, University of Aukland, Aukland, NZ.
¹⁸ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁹ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
²⁰ Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands.
²¹ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
²² Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, F-91057, Evry, France.
²³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁴ Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont, USA.
²⁵ INSERM, UMR_S 744, Institut Pasteur de Lille; Université de Lille Nord de France, F-59019, Lille, France.
²⁶ Department of Medicine, Boston University, Boston, MA, USA.
²⁷ Centre Hospitalier Régional Universitaire de Lille, F-59037, Lille, France.
²⁸ Department of Pathology, University of Vermont, Burlington, VT, USA.
²⁹ Departments of Biochemistry and Pathology, University of Vermont, Burlington, VT, USA.
³⁰ Human Genetics Center and Human Genome Sequencing Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
³¹ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³² INSERM, UMR_S 937, ICAN Institute for Cardiometabolism and Nutrition, University Pierre & Marie Curie, Paris 06, F-75013, Paris, France.
³³ Drug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands.

^# Contributed equally.

PMID: 23650146
PMCID: PMC3990406
DOI: 10.1002/gepi.21731

Abstract

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

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Figures

**Figure 1**
Manhattan plot showing the genome-wide −log₁₀ p-values against physical position for total incident VTE in CHARGE.

**Figure 2**
Regional association plot for total incident VTE at the F5 region on chromosome 1 in CHARGE. The horizontal line indicates the genome-wide significance threshold of p=5.0×10⁻⁸. The top SNP is shown by blue triangle. The color of the remaining SNPs reflects the r² with the top SNP based on the HapMap CEU data with the following color scheme: r²≥0.8 – red, 0.5 ≤ r² < 0.8 - orange, 0.2 ≤ r² < 0.5 - yellow, and r² < 0.2 - white. The light blue line represents the recombination rate (the y axis at right side) based on the data from the HapMap CEU population. Gene annotations are shown under the x axis.

**Figure 3**
Regional association plot for total incident VTE at the *ABO* region on chromosome 9 in CHARGE.

**Figure 4**
Regional association plot for total incident VTE at the *FGG* region on chromosome 4 in CHARGE.

**Figure 5**
Regional association plot for total incident VTE at the *F11* region on chromosome 4 in CHARGE.

See this image and copyright information in PMC

References

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A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium

Affiliations

A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous