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

View ORCID ProfileAndrei-Emil Constantinescu, View ORCID ProfileCaroline J Bull, View ORCID ProfileLucy J Goudswaard, Jie Zheng, Benjamin Elsworth, View ORCID ProfileNicholas J Timpson, Samantha F Moore, View ORCID ProfileIngeborg Hers, View ORCID ProfileEmma E Vincent
doi: https://doi.org/10.1101/476135
Andrei-Emil Constantinescu
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
3School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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  • ORCID record for Andrei-Emil Constantinescu
Caroline J Bull
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
3School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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Lucy J Goudswaard
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
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Jie Zheng
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
5Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
6Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Benjamin Elsworth
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
7Our Future Health. Registered office: 2 New Bailey, 6 Stanley Street, Manchester M3 5GS.
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Nicholas J Timpson
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
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Samantha F Moore
4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
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Ingeborg Hers
4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
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  • For correspondence: emma.vincent@bristol.ac.uk i.hers@bristol.ac.uk
Emma E Vincent
1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
2Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
3School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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  • For correspondence: emma.vincent@bristol.ac.uk i.hers@bristol.ac.uk
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Summary

Background 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.

Objective To leverage publicly available genetic summary association statistics to identify causal risk factors for DVT.

Methods & Results 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, chronic obstructive pulmonary disease (COPD) 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.

Conclusion Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins, COPD and BMI enhance the risk of DVT. The circulating protein PAI-1 has furthermore a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Updated text for all manuscript sections to reflect additional work done. This includes updates to the MR-PheWAS analysis, and the addition of the MR mediation anaylsis using pQTL data, and the addition of the conditional and colocalization analyses. Added figure to describe the study. Added figure to describe the pQTL MR. Added figures to describe colocalization analysis. Updated figures to reflect updated work for the initial analysis. Added supplementary tables and figures. Added new co-author. Updated abstract.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 06, 2022.
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A phenome-wide approach to identify causal risk factors for deep vein thrombosis
Andrei-Emil Constantinescu, Caroline J Bull, Lucy J Goudswaard, Jie Zheng, Benjamin Elsworth, Nicholas J Timpson, Samantha F Moore, Ingeborg Hers, Emma E Vincent
bioRxiv 476135; doi: https://doi.org/10.1101/476135
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A phenome-wide approach to identify causal risk factors for deep vein thrombosis
Andrei-Emil Constantinescu, Caroline J Bull, Lucy J Goudswaard, Jie Zheng, Benjamin Elsworth, Nicholas J Timpson, Samantha F Moore, Ingeborg Hers, Emma E Vincent
bioRxiv 476135; doi: https://doi.org/10.1101/476135

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