A phenome-wide approach to identify causal risk factors for deep vein thrombosis

Andrei Constantinescu; Caroline J Bull; Lucy J Goudswaard; Jie Zheng; Benjamin Elsworth; Nicholas John  Timpson; Samantha Frances Moore; Ingeborg Hers; Emma E Vincent

doi:10.1186/s12920-023-01710-9

A phenome-wide approach to identify causal risk factors for deep vein thrombosis

Andrei Constantinescu^*, Caroline J Bull, Lucy J Goudswaard, Jie Zheng, Benjamin Elsworth, Nicholas John Timpson, Samantha Frances Moore, Ingeborg Hers, Emma E Vincent

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

1 Citation (Scopus)

Abstract

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index—BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

Original language	English
Article number	284
Journal	BMC Medical Genomics
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s12920-023-01710-9
Publication status	Published - 11 Nov 2023

Bibliographical note

Funding Information:
AC acknowledges funding from grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. NJT is the PI of the Avon Longitudinal Study of Parents and Children (Medical Research Council & Wellcome Trust 217065/Z/19/Z) and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001). NJT acknowledges funding from the Wellcome Trust (202802/Z/16/Z). EEV, CJB, and NJT acknowledge funding by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). NJT, EEV and CJB work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 & MC_UU_00011/4) and the University of Bristol. EEV and CJB are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). LJG is supported by a BHF Accelerator Award Transition Fellowship (AA/18/1/34219). IH and SM acknowledge funding by the BHF (PG/16/3/31833 and PG/16/21/32083) and EPSRC Prostanoid programme (EP/M012530/1). SM acknowledges funding from the MRC. JZ is supported by Shanghai Thousand Talents Program and the National Health Commission of the PR China (SBF006\1117). CJB acknowledges funding from Health Data Research UK, an independent registered charity (number 1194431). BE acknowledges funding from Our Future Health, a company limited by guarantee registered in England and Wales (number 12212468) and a charity registered with the Charity Commission for England and Wales (charity number 1189681) and OSCR, Scottish Charity Regulator (charity number SC050917). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and EEV and IH will serve as guarantors for the contents of this paper. This research was funded in whole, or in part, by the Wellcome Trust (217065/Z/19/Z & 202802/Z/16/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ); This research was specifically funded by Wellcome Trust WT091310. This work was also supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (ISSF 204813/Z/16/Z). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

Publisher Copyright:
© 2023, The Author(s).

Research Groups and Themes

ICEP

Keywords

Mendelian randomization
Deep vein thrombosis
ALSPAC
Protein quantitative trait loci
genome-wide association study (GWAS)

Access to Document

10.1186/s12920-023-01710-9Licence: CC BY

https://rdcu.be/dqR0hLicence: CC BY

Handle.net

Persistent link

1 Finished
1 Active

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research
IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Using genetic data to determine the effect of routinely measured blood cell traits on disease
Constantinescu, A. (Author), Vincent, E. (Supervisor), Timpson, N. (Supervisor), Bull, C. (Supervisor) & Dayan, C. (Supervisor), 3 Oct 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)

File

Cite this

@article{12e5cd61df4d4005b02b3908a80d2a87,

title = "A phenome-wide approach to identify causal risk factors for deep vein thrombosis",

abstract = "Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index—BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.",

keywords = "Mendelian randomization, Deep vein thrombosis, ALSPAC, Protein quantitative trait loci, genome-wide association study (GWAS)",

author = "Andrei Constantinescu and Bull, {Caroline J} and Goudswaard, {Lucy J} and Jie Zheng and Benjamin Elsworth and Timpson, {Nicholas John} and Moore, {Samantha Frances} and Ingeborg Hers and Vincent, {Emma E}",

note = "Funding Information: AC acknowledges funding from grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. NJT is the PI of the Avon Longitudinal Study of Parents and Children (Medical Research Council & Wellcome Trust 217065/Z/19/Z) and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001). NJT acknowledges funding from the Wellcome Trust (202802/Z/16/Z). EEV, CJB, and NJT acknowledge funding by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). NJT, EEV and CJB work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 & MC_UU_00011/4) and the University of Bristol. EEV and CJB are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). LJG is supported by a BHF Accelerator Award Transition Fellowship (AA/18/1/34219). IH and SM acknowledge funding by the BHF (PG/16/3/31833 and PG/16/21/32083) and EPSRC Prostanoid programme (EP/M012530/1). SM acknowledges funding from the MRC. JZ is supported by Shanghai Thousand Talents Program and the National Health Commission of the PR China (SBF006\1117). CJB acknowledges funding from Health Data Research UK, an independent registered charity (number 1194431). BE acknowledges funding from Our Future Health, a company limited by guarantee registered in England and Wales (number 12212468) and a charity registered with the Charity Commission for England and Wales (charity number 1189681) and OSCR, Scottish Charity Regulator (charity number SC050917). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and EEV and IH will serve as guarantors for the contents of this paper. This research was funded in whole, or in part, by the Wellcome Trust (217065/Z/19/Z & 202802/Z/16/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ); This research was specifically funded by Wellcome Trust WT091310. This work was also supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (ISSF 204813/Z/16/Z). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = nov,

day = "11",

doi = "10.1186/s12920-023-01710-9",

language = "English",

volume = "16",

journal = "BMC Medical Genomics",

issn = "1755-8794",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - A phenome-wide approach to identify causal risk factors for deep vein thrombosis

AU - Constantinescu, Andrei

AU - Bull, Caroline J

AU - Goudswaard, Lucy J

AU - Zheng, Jie

AU - Elsworth, Benjamin

AU - Timpson, Nicholas John

AU - Moore, Samantha Frances

AU - Hers, Ingeborg

AU - Vincent, Emma E

N1 - Funding Information: AC acknowledges funding from grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. NJT is the PI of the Avon Longitudinal Study of Parents and Children (Medical Research Council & Wellcome Trust 217065/Z/19/Z) and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001). NJT acknowledges funding from the Wellcome Trust (202802/Z/16/Z). EEV, CJB, and NJT acknowledge funding by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). NJT, EEV and CJB work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 & MC_UU_00011/4) and the University of Bristol. EEV and CJB are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). LJG is supported by a BHF Accelerator Award Transition Fellowship (AA/18/1/34219). IH and SM acknowledge funding by the BHF (PG/16/3/31833 and PG/16/21/32083) and EPSRC Prostanoid programme (EP/M012530/1). SM acknowledges funding from the MRC. JZ is supported by Shanghai Thousand Talents Program and the National Health Commission of the PR China (SBF006\1117). CJB acknowledges funding from Health Data Research UK, an independent registered charity (number 1194431). BE acknowledges funding from Our Future Health, a company limited by guarantee registered in England and Wales (number 12212468) and a charity registered with the Charity Commission for England and Wales (charity number 1189681) and OSCR, Scottish Charity Regulator (charity number SC050917). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and EEV and IH will serve as guarantors for the contents of this paper. This research was funded in whole, or in part, by the Wellcome Trust (217065/Z/19/Z & 202802/Z/16/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ); This research was specifically funded by Wellcome Trust WT091310. This work was also supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (ISSF 204813/Z/16/Z). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. Publisher Copyright: © 2023, The Author(s).

PY - 2023/11/11

Y1 - 2023/11/11

N2 - Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index—BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

AB - Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index—BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

KW - Mendelian randomization

KW - Deep vein thrombosis

KW - ALSPAC

KW - Protein quantitative trait loci

KW - genome-wide association study (GWAS)

U2 - 10.1186/s12920-023-01710-9

DO - 10.1186/s12920-023-01710-9

M3 - Article (Academic Journal)

C2 - 37951941

SN - 1755-8794

VL - 16

JO - BMC Medical Genomics

JF - BMC Medical Genomics

IS - 1

M1 - 284

ER -

A phenome-wide approach to identify causal risk factors for deep vein thrombosis

Abstract

Bibliographical note

Research Groups and Themes

Keywords

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Student theses

Using genetic data to determine the effect of routinely measured blood cell traits on disease

Cite this