Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes

the INVENT consortium

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. Summary: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case–control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29–1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10–1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11, and observed secondary signals in F5 and CYP4V2–KLKB1–F11 that warrant replication and fine-mapping in larger studies.

Original languageEnglish
Pages (from-to)2432-2441
JournalJournal of Thrombosis and Haemostasis
Volume16
Issue number12
DOIs
Publication statusPublished - 2018

Fingerprint

Venous Thrombosis
Genes
Hemostasis
Thrombophilia
Gene Frequency
Venous Thromboembolism
DNA Sequence Analysis

Keywords

  • deep vein thrombosis
  • DNA sequencing
  • genetics
  • risk factors
  • single-nucleotide polymorphisms

ASJC Scopus subject areas

  • Hematology

Cite this

Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis : a study of 734 genes. / the INVENT consortium.

In: Journal of Thrombosis and Haemostasis, Vol. 16, No. 12, 2018, p. 2432-2441.

Research output: Contribution to journalArticle

@article{a89139152f3e4dabb91d8f93d3eda1a1,
title = "Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes",
abstract = "Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. Summary: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case–control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1{\%}) and gene-based tests for rare variants (MAF ≤ 1{\%}), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95{\%} confidence interval [CI] 1.29–1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95{\%} CI 1.10–1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11, and observed secondary signals in F5 and CYP4V2–KLKB1–F11 that warrant replication and fine-mapping in larger studies.",
keywords = "deep vein thrombosis, DNA sequencing, genetics, risk factors, single-nucleotide polymorphisms",
author = "{the INVENT consortium} and {de Haan}, {H. G.} and {van Hylckama Vlieg}, A. and Lotta, {L. A.} and Gorski, {M. M.} and P. Bucciarelli and I. Martinelli and Baglin, {T. P.} and F. Peyvandi and Rosendaal, {F. R.} and P. Amouyel and {de Andrade}, M. and S. Basu and C. Berr and Brody, {J. A.} and Chasman, {D. I.} and Dartigues, {J. F.} and Folsom, {A. R.} and M. Germain and J. Heit and J. Houwing-Duitermaat and C. Kabrhel and P. Kraft and {Le Gal}, G. and S. Lindstr{\"o}m and R. Monajemi and Morange, {P. E.} and Psaty, {B. M.} and Reitsma, {P. H.} and Ridker, {P. M.} and Rose, {L. M.} and N. Saut and E. Slagboom and D. Smadja and Smith, {N. L.} and P. Suchon and W. Tang and Taylor, {K. D.} and Tr{\'e}gou{\"e}t, {D. A.} and C. Tzourio and {de Visser}, {M. C.H.} and Weng, {L. C.} and Wiggins, {K. L.}",
year = "2018",
doi = "10.1111/jth.14279",
language = "English",
volume = "16",
pages = "2432--2441",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "12",

}

TY - JOUR

T1 - Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis

T2 - a study of 734 genes

AU - the INVENT consortium

AU - de Haan, H. G.

AU - van Hylckama Vlieg, A.

AU - Lotta, L. A.

AU - Gorski, M. M.

AU - Bucciarelli, P.

AU - Martinelli, I.

AU - Baglin, T. P.

AU - Peyvandi, F.

AU - Rosendaal, F. R.

AU - Amouyel, P.

AU - de Andrade, M.

AU - Basu, S.

AU - Berr, C.

AU - Brody, J. A.

AU - Chasman, D. I.

AU - Dartigues, J. F.

AU - Folsom, A. R.

AU - Germain, M.

AU - Heit, J.

AU - Houwing-Duitermaat, J.

AU - Kabrhel, C.

AU - Kraft, P.

AU - Le Gal, G.

AU - Lindström, S.

AU - Monajemi, R.

AU - Morange, P. E.

AU - Psaty, B. M.

AU - Reitsma, P. H.

AU - Ridker, P. M.

AU - Rose, L. M.

AU - Saut, N.

AU - Slagboom, E.

AU - Smadja, D.

AU - Smith, N. L.

AU - Suchon, P.

AU - Tang, W.

AU - Taylor, K. D.

AU - Trégouët, D. A.

AU - Tzourio, C.

AU - de Visser, M. C.H.

AU - Weng, L. C.

AU - Wiggins, K. L.

PY - 2018

Y1 - 2018

N2 - Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. Summary: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case–control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29–1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10–1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11, and observed secondary signals in F5 and CYP4V2–KLKB1–F11 that warrant replication and fine-mapping in larger studies.

AB - Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. Summary: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case–control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ≥ 1%) and gene-based tests for rare variants (MAF ≤ 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29–1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10–1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA–FGG, and CYP4V2–KLKB1–F11, and observed secondary signals in F5 and CYP4V2–KLKB1–F11 that warrant replication and fine-mapping in larger studies.

KW - deep vein thrombosis

KW - DNA sequencing

KW - genetics

KW - risk factors

KW - single-nucleotide polymorphisms

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DO - 10.1111/jth.14279

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JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

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