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Consequences of natural perturbations in the human plasma proteome

Benjamin B. Sun, Joseph C. Maranville, James E. Peters, David Stacey, James R. Staley, James Blackshaw, Stephen Burgess, Tao Jiang, Ellie Paige, Praveen Surendran, Clare Oliver-Williams, Mihir A. Kamat, Bram P. Prins, Sheri K. Wilcox, Erik S. Zimmerman, An Chi, Narinder Bansal, Sarah L. Spain, Angela M. Wood, Nicholas W. Morrell, John R. Bradley, Nebojsa Janjic, David J. Roberts, Willem H. Ouwehand, John A. Todd, Nicole Soranzo, Karsten Suhre, Dirk S. Paul, Caroline S. Fox, Robert M. Plenge, John Danesh, Heiko Runz, Adam S. Butterworth
doi: https://doi.org/10.1101/134551
Benjamin B. Sun
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Joseph C. Maranville
2MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA.
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James E. Peters
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
3British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
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David Stacey
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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James R. Staley
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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James Blackshaw
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Stephen Burgess
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
4MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK.
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Tao Jiang
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Ellie Paige
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Praveen Surendran
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Clare Oliver-Williams
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Mihir A. Kamat
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Bram P. Prins
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Sheri K. Wilcox
5SomaLogic Inc., Boulder, Colorado 80301, USA.
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Erik S. Zimmerman
5SomaLogic Inc., Boulder, Colorado 80301, USA.
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An Chi
2MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA.
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Narinder Bansal
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
6Perinatal Institute, Birmingham B15 3BU, UK.
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Sarah L. Spain
7Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1RQ, UK.
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Angela M. Wood
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Nicholas W. Morrell
8Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
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John R. Bradley
9NIHR Cambridge Biomedical Research Centre / BioResource, Cambridge University Hospitals, Cambridge CB2 0QQ, UK.
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Nebojsa Janjic
5SomaLogic Inc., Boulder, Colorado 80301, USA.
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David J. Roberts
10National Health Service (NHS) Blood and Transplant and Radcliffe Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
11BRC Haematology Theme and Department of Haematology, Churchill Hospital, Oxford OX3 7LE, UK.
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Willem H. Ouwehand
3British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
12Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
13National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
14Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1RQ, UK.
15NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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John A. Todd
16JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
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Nicole Soranzo
3British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
12Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
14Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1RQ, UK.
15NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Karsten Suhre
17Department of Physiology and Biophysics, Weill Cornell Medicine - Qatar, PO 24144 Doha, Qatar.
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Dirk S. Paul
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Caroline S. Fox
2MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA.
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Robert M. Plenge
2MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA.
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John Danesh
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
3British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
14Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1RQ, UK.
15NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Heiko Runz
2MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA.
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Adam S. Butterworth
1MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
15NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
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Abstract

Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels. Here we reveal the genetic architecture of the human plasma proteome, testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we introduce an approach that links naturally occurring genetic variation with biological, disease, and drug databases. We provide insights into pathogenesis by uncovering the molecular effects of disease-associated variants. We identify causal roles for protein biomarkers in disease through Mendelian randomization analysis. Our results reveal new drug targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

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Posted May 05, 2017.
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Consequences of natural perturbations in the human plasma proteome
Benjamin B. Sun, Joseph C. Maranville, James E. Peters, David Stacey, James R. Staley, James Blackshaw, Stephen Burgess, Tao Jiang, Ellie Paige, Praveen Surendran, Clare Oliver-Williams, Mihir A. Kamat, Bram P. Prins, Sheri K. Wilcox, Erik S. Zimmerman, An Chi, Narinder Bansal, Sarah L. Spain, Angela M. Wood, Nicholas W. Morrell, John R. Bradley, Nebojsa Janjic, David J. Roberts, Willem H. Ouwehand, John A. Todd, Nicole Soranzo, Karsten Suhre, Dirk S. Paul, Caroline S. Fox, Robert M. Plenge, John Danesh, Heiko Runz, Adam S. Butterworth
bioRxiv 134551; doi: https://doi.org/10.1101/134551
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Consequences of natural perturbations in the human plasma proteome
Benjamin B. Sun, Joseph C. Maranville, James E. Peters, David Stacey, James R. Staley, James Blackshaw, Stephen Burgess, Tao Jiang, Ellie Paige, Praveen Surendran, Clare Oliver-Williams, Mihir A. Kamat, Bram P. Prins, Sheri K. Wilcox, Erik S. Zimmerman, An Chi, Narinder Bansal, Sarah L. Spain, Angela M. Wood, Nicholas W. Morrell, John R. Bradley, Nebojsa Janjic, David J. Roberts, Willem H. Ouwehand, John A. Todd, Nicole Soranzo, Karsten Suhre, Dirk S. Paul, Caroline S. Fox, Robert M. Plenge, John Danesh, Heiko Runz, Adam S. Butterworth
bioRxiv 134551; doi: https://doi.org/10.1101/134551

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