Genetics of varicose veins reveals polygenic architecture and genetic overlap with arterial and venous disease

Michael G. Levin; Jennifer E. Huffman; Anurag Verma; Kyle A. Sullivan; Alexis A. Rodriguez; David Kainer; Michael R. Garvin; Matthew Lane; Mikaela Cashman; J. Izaak Miller; Hyejung Won; Binglan Li; Yuan Luo; Gail P. Jarvik; Hakon Hakonarson; Elizabeth A. Jasper; Alexander G. Bick; Philip S. Tsao; Marylyn D. Ritchie; Daniel A. Jacobson; Ravi K. Madduri; Scott M. Damrauer

doi:10.1038/s44161-022-00196-5

Genetics of varicose veins reveals polygenic architecture and genetic overlap with arterial and venous disease

Michael G. Levin, Jennifer E. Huffman, Anurag Verma, Kyle A. Sullivan, Alexis A. Rodriguez, David Kainer, Michael R. Garvin, Matthew Lane, Mikaela Cashman, J. Izaak Miller, Hyejung Won, Binglan Li, Yuan Luo, Gail P. Jarvik, Hakon Hakonarson, Elizabeth A. Jasper, Alexander G. Bick, Philip S. Tsao, Marylyn D. Ritchie, Daniel A. JacobsonRavi K. Madduri, Scott M. Damrauer

Computational and Predictive Biology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants to varicose veins using data from the Veterans Affairs Million Veteran Program and four other large biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases and dozens of anthropometric factors. Using Mendelian randomization, we prioritized therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling and angiogenesis. These findings may facilitate future efforts to develop nonsurgical therapies for varicose veins.

Original language	English
Pages (from-to)	44-57
Number of pages	14
Journal	Nature Cardiovascular Research
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s44161-022-00196-5
State	Published - Jan 2023

Funding

We thank the participants of the VA Million Veteran Program, UK Biobank, eMERGE, FinnGen and BioBank Japan studies. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by an award from the Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) initiative to S.M.D., P.S.T. and R.K.M. This publication does not represent the views of the Department of Veteran Affairs or the US Government. M.G.L. is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania and the NIH/NHLBI National Research Service Award postdoctoral fellowship (grant no. T32HL007843). S.M.D. is supported by the US Department of Veterans Affairs award no. IK2-CX001780. This publication does not represent the views of the Department of Veterans Affairs or the US Government. D.A.J., K.A.S., D.K., M.R.G., M.L., M.C. and J.I.M. are supported by funding from the Million Veteran Program Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) initiative and NIH grants no. DA051908 and no. DA051913. eMERGE is supported by grant no. U01HG8657 (University of Washington); grant no. U01HG8685 (Brigham and Women’s Hospital); grant no. U01HG8672 (Vanderbilt University Medical Center); grant no. U01HG8666 (Cincinnati Children’s Hospital Medical Center); grant no. U01HG6379 (Mayo Clinic); grant no. U01HG8679 (Geisinger Clinic); grant no. U01HG8680 (Columbia University Health Sciences); grant no. U01HG8684 (Children’s Hospital of Philadelphia); grant no. U01HG8673 (Northwestern University); grant no. U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); grant no. U01HG8676 (Partners Healthcare/Broad Institute); and grant no. U01HG8664 (Baylor College of Medicine). This research used resources of the Oak Ridge Leadership Computing Facility, which is a DOE Office of Science User Facility supported under Contract no. DE-AC05-00OR22725. This manuscript has been coauthored by UT-Battelle, LLC under contract no. DE-AC05-00OR22725 with the US Department of Energy. The US Government retains, and the publisher, by accepting the article for publication, acknowledges that the US Government retains, a nonexclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan , last accessed 16 September 2020). E.A.J. is supported by the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) career development program (grant no. K12HD043483). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the participants of the VA Million Veteran Program, UK Biobank, eMERGE, FinnGen and BioBank Japan studies. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by an award from the Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) initiative to S.M.D., P.S.T. and R.K.M. This publication does not represent the views of the Department of Veteran Affairs or the US Government. M.G.L. is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania and the NIH/NHLBI National Research Service Award postdoctoral fellowship (grant no. T32HL007843). S.M.D. is supported by the US Department of Veterans Affairs award no. IK2-CX001780. This publication does not represent the views of the Department of Veterans Affairs or the US Government. D.A.J., K.A.S., D.K., M.R.G., M.L., M.C. and J.I.M. are supported by funding from the Million Veteran Program Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) initiative and NIH grants no. DA051908 and no. DA051913. eMERGE is supported by grant no. U01HG8657 (University of Washington); grant no. U01HG8685 (Brigham and Women’s Hospital); grant no. U01HG8672 (Vanderbilt University Medical Center); grant no. U01HG8666 (Cincinnati Children’s Hospital Medical Center); grant no. U01HG6379 (Mayo Clinic); grant no. U01HG8679 (Geisinger Clinic); grant no. U01HG8680 (Columbia University Health Sciences); grant no. U01HG8684 (Children’s Hospital of Philadelphia); grant no. U01HG8673 (Northwestern University); grant no. U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); grant no. U01HG8676 (Partners Healthcare/Broad Institute); and grant no. U01HG8664 (Baylor College of Medicine). This research used resources of the Oak Ridge Leadership Computing Facility, which is a DOE Office of Science User Facility supported under Contract no. DE-AC05-00OR22725. This manuscript has been coauthored by UT-Battelle, LLC under contract no. DE-AC05-00OR22725 with the US Department of Energy. The US Government retains, and the publisher, by accepting the article for publication, acknowledges that the US Government retains, a nonexclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan , last accessed 16 September 2020). E.A.J. is supported by the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) career development program (grant no. K12HD043483). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funders	Funder number
BioBank
Building Interdisciplinary Research Careers in Women’s Health	K12HD043483
DOE Public Access Plan
FinnGen
Million Veteran Program
VA Million Veteran Program
Veteran Affairs or the US Government
Veterans Affairs or the US Government
eMERGE
National Institutes of Health
U.S. Department of Energy
National Heart, Lung, and Blood Institute	T32HL007843
U.S. Department of Veterans Affairs	DA051913, U01HG8657, DA051908, IK2-CX001780
Mayo Clinic	U01HG8676, U01HG8664, U01HG8679, U01HG8701, U01HG8680, U01HG8673, U01HG8684
Office of Science	DE-AC05-00OR22725
Office of Research and Development
Health Services Research and Development
University of Washington	U01HG8666, U01HG8685, U01HG6379, U01HG8672
Baylor College of Medicine
Perelman School of Medicine, University of Pennsylvania
Institute for Translational Medicine and Therapeutics
Government of South Australia
UT-Battelle

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10.1038/s44161-022-00196-5

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Levin, M. G., Huffman, J. E., Verma, A., Sullivan, K. A., Rodriguez, A. A., Kainer, D., Garvin, M. R., Lane, M., Cashman, M., Miller, J. I., Won, H., Li, B., Luo, Y., Jarvik, G. P., Hakonarson, H., Jasper, E. A., Bick, A. G., Tsao, P. S., Ritchie, M. D., ... Damrauer, S. M. (2023). Genetics of varicose veins reveals polygenic architecture and genetic overlap with arterial and venous disease. Nature Cardiovascular Research, 2(1), 44-57. https://doi.org/10.1038/s44161-022-00196-5

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title = "Genetics of varicose veins reveals polygenic architecture and genetic overlap with arterial and venous disease",

abstract = "Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants to varicose veins using data from the Veterans Affairs Million Veteran Program and four other large biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases and dozens of anthropometric factors. Using Mendelian randomization, we prioritized therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling and angiogenesis. These findings may facilitate future efforts to develop nonsurgical therapies for varicose veins.",

author = "Levin, {Michael G.} and Huffman, {Jennifer E.} and Anurag Verma and Sullivan, {Kyle A.} and Rodriguez, {Alexis A.} and David Kainer and Garvin, {Michael R.} and Matthew Lane and Mikaela Cashman and Miller, {J. Izaak} and Hyejung Won and Binglan Li and Yuan Luo and Jarvik, {Gail P.} and Hakon Hakonarson and Jasper, {Elizabeth A.} and Bick, {Alexander G.} and Tsao, {Philip S.} and Ritchie, {Marylyn D.} and Jacobson, {Daniel A.} and Madduri, {Ravi K.} and Damrauer, {Scott M.}",

note = "Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2023",

month = jan,

doi = "10.1038/s44161-022-00196-5",

language = "English",

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Levin, MG, Huffman, JE, Verma, A, Sullivan, KA, Rodriguez, AA, Kainer, D, Garvin, MR, Lane, M, Cashman, M, Miller, JI, Won, H, Li, B, Luo, Y, Jarvik, GP, Hakonarson, H, Jasper, EA, Bick, AG, Tsao, PS, Ritchie, MD, Jacobson, DA, Madduri, RK & Damrauer, SM 2023, 'Genetics of varicose veins reveals polygenic architecture and genetic overlap with arterial and venous disease', Nature Cardiovascular Research, vol. 2, no. 1, pp. 44-57. https://doi.org/10.1038/s44161-022-00196-5

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N2 - Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants to varicose veins using data from the Veterans Affairs Million Veteran Program and four other large biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases and dozens of anthropometric factors. Using Mendelian randomization, we prioritized therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling and angiogenesis. These findings may facilitate future efforts to develop nonsurgical therapies for varicose veins.

AB - Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants to varicose veins using data from the Veterans Affairs Million Veteran Program and four other large biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases and dozens of anthropometric factors. Using Mendelian randomization, we prioritized therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling and angiogenesis. These findings may facilitate future efforts to develop nonsurgical therapies for varicose veins.

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Genetics of varicose veins reveals polygenic architecture and genetic overlap with arterial and venous disease

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