A Genome-Wide Association Study for Venous Thromboembolism

The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Weihong Tang, Martina Teichert, Daniel I. Chasman, John A. Heit, Pierre Emmanuel Morange, Guo Li, Nathan Pankratz, Frank W. Leebeek, Guillaume Paré, Mariza De Andrade, Christophe Tzourio, Bruce M. Psaty, Saonli Basu, Rikje Ruiter, Lynda Rose, Sebastian M. Armasu, Thomas Lumley, Susan R. Heckbert, André G. Uitterlinden, Mark Lathrop & 20 others Kenneth M. Rice, Mary Cushman, Albert Hofman, Jean Charles Lambert, Nicole L. Glazer, James S. Pankow, Jacqueline C. Witteman, Philippe Amouyel, Joshua C. Bis, Edwin G. Bovill, Xiaoxiao Kong, Russell P. Tracy, Eric Boerwinkle, Jerome I. Rotter, David Alexandre Trégouët, Daan W. Loth, Bruno H Ch Stricker, Paul M. Ridker, Aaron R. Folsom, Nicholas L. Smith

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)512-521
Number of pages10
JournalGenetic Epidemiology
Volume37
Issue number5
DOIs
StatePublished - Jul 2013

Fingerprint

Genome-Wide Association Study
Venous Thromboembolism
Epidemiology
Single Nucleotide Polymorphism
Research
Genome
HapMap Project
Meta-Analysis
Case-Control Studies
Hospitalization
Genotype
Mortality
Genes

Keywords

  • Genetic epidemiology
  • Genetics
  • Genome-wide association
  • Venous thrombosis

ASJC Scopus subject areas

  • Genetics(clinical)
  • Epidemiology

Cite this

A Genome-Wide Association Study for Venous Thromboembolism : The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. / Tang, Weihong; Teichert, Martina; Chasman, Daniel I.; Heit, John A.; Morange, Pierre Emmanuel; Li, Guo; Pankratz, Nathan; Leebeek, Frank W.; Paré, Guillaume; De Andrade, Mariza; Tzourio, Christophe; Psaty, Bruce M.; Basu, Saonli; Ruiter, Rikje; Rose, Lynda; Armasu, Sebastian M.; Lumley, Thomas; Heckbert, Susan R.; Uitterlinden, André G.; Lathrop, Mark; Rice, Kenneth M.; Cushman, Mary; Hofman, Albert; Lambert, Jean Charles; Glazer, Nicole L.; Pankow, James S.; Witteman, Jacqueline C.; Amouyel, Philippe; Bis, Joshua C.; Bovill, Edwin G.; Kong, Xiaoxiao; Tracy, Russell P.; Boerwinkle, Eric; Rotter, Jerome I.; Trégouët, David Alexandre; Loth, Daan W.; Stricker, Bruno H Ch; Ridker, Paul M.; Folsom, Aaron R.; Smith, Nicholas L.

In: Genetic Epidemiology, Vol. 37, No. 5, 07.2013, p. 512-521.

Research output: Contribution to journalArticle

Tang, W, Teichert, M, Chasman, DI, Heit, JA, Morange, PE, Li, G, Pankratz, N, Leebeek, FW, Paré, G, De Andrade, M, Tzourio, C, Psaty, BM, Basu, S, Ruiter, R, Rose, L, Armasu, SM, Lumley, T, Heckbert, SR, Uitterlinden, AG, Lathrop, M, Rice, KM, Cushman, M, Hofman, A, Lambert, JC, Glazer, NL, Pankow, JS, Witteman, JC, Amouyel, P, Bis, JC, Bovill, EG, Kong, X, Tracy, RP, Boerwinkle, E, Rotter, JI, Trégouët, DA, Loth, DW, Stricker, BHC, Ridker, PM, Folsom, AR & Smith, NL 2013, 'A Genome-Wide Association Study for Venous Thromboembolism: The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium', Genetic Epidemiology, vol. 37, no. 5, pp. 512-521. https://doi.org/10.1002/gepi.21731
Tang, Weihong ; Teichert, Martina ; Chasman, Daniel I. ; Heit, John A. ; Morange, Pierre Emmanuel ; Li, Guo ; Pankratz, Nathan ; Leebeek, Frank W. ; Paré, Guillaume ; De Andrade, Mariza ; Tzourio, Christophe ; Psaty, Bruce M. ; Basu, Saonli ; Ruiter, Rikje ; Rose, Lynda ; Armasu, Sebastian M. ; Lumley, Thomas ; Heckbert, Susan R. ; Uitterlinden, André G. ; Lathrop, Mark ; Rice, Kenneth M. ; Cushman, Mary ; Hofman, Albert ; Lambert, Jean Charles ; Glazer, Nicole L. ; Pankow, James S. ; Witteman, Jacqueline C. ; Amouyel, Philippe ; Bis, Joshua C. ; Bovill, Edwin G. ; Kong, Xiaoxiao ; Tracy, Russell P. ; Boerwinkle, Eric ; Rotter, Jerome I. ; Trégouët, David Alexandre ; Loth, Daan W. ; Stricker, Bruno H Ch ; Ridker, Paul M. ; Folsom, Aaron R. ; Smith, Nicholas L. / A Genome-Wide Association Study for Venous Thromboembolism : The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. In: Genetic Epidemiology. 2013 ; Vol. 37, No. 5. pp. 512-521.
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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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T1 - A Genome-Wide Association Study for Venous Thromboembolism

T2 - The Extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

AU - Tang, Weihong

AU - Teichert, Martina

AU - Chasman, Daniel I.

AU - Heit, John A.

AU - Morange, Pierre Emmanuel

AU - Li, Guo

AU - Pankratz, Nathan

AU - Leebeek, Frank W.

AU - Paré, Guillaume

AU - De Andrade, Mariza

AU - Tzourio, Christophe

AU - Psaty, Bruce M.

AU - Basu, Saonli

AU - Ruiter, Rikje

AU - Rose, Lynda

AU - Armasu, Sebastian M.

AU - Lumley, Thomas

AU - Heckbert, Susan R.

AU - Uitterlinden, André G.

AU - Lathrop, Mark

AU - Rice, Kenneth M.

AU - Cushman, Mary

AU - Hofman, Albert

AU - Lambert, Jean Charles

AU - Glazer, Nicole L.

AU - Pankow, James S.

AU - Witteman, Jacqueline C.

AU - Amouyel, Philippe

AU - Bis, Joshua C.

AU - Bovill, Edwin G.

AU - Kong, Xiaoxiao

AU - Tracy, Russell P.

AU - Boerwinkle, Eric

AU - Rotter, Jerome I.

AU - Trégouët, David Alexandre

AU - Loth, Daan W.

AU - Stricker, Bruno H Ch

AU - Ridker, Paul M.

AU - Folsom, Aaron R.

AU - Smith, Nicholas L.

PY - 2013/7

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N2 - 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.

AB - 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.

KW - Genetic epidemiology

KW - Genetics

KW - Genome-wide association

KW - Venous thrombosis

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