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Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

View ORCID ProfileJie Zheng, Valeriia Haberland, Denis Baird, Venexia Walker, Philip Haycock, Mark Hurle, Alex Gutteridge, Pau Erola, Yi Liu, Shan Luo, Jamie Robinson, Tom G. Richardson, James R. Staley, Benjamin Elsworth, Stephen Burgess, Benjamin B. Sun, John Danesh, Heiko Runz, Joseph C. Maranville, Hannah M. Martin, James Yarmolinsky, Charles Laurin, Michael V. Holmes, Jimmy Liu, Karol Estrada, Rita Santos, Linda McCarthy, Dawn Waterworth, Matthew R. Nelson, Gibran Hemani, George Davey Smith, Adam S. Butterworth, Robert A. Scott, Tom R. Gaunt
doi: https://doi.org/10.1101/627398
Jie Zheng
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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  • ORCID record for Jie Zheng
  • For correspondence: epxjz@bristol.ac.uk
Valeriia Haberland
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Denis Baird
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Venexia Walker
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Philip Haycock
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Mark Hurle
2Genetics, GlaxoSmithKline, Collegeville, PA, USA
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Alex Gutteridge
3GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
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Pau Erola
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Yi Liu
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Shan Luo
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
4School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China
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Jamie Robinson
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Tom G. Richardson
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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James R. Staley
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
5MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
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Benjamin Elsworth
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Stephen Burgess
5MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
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Benjamin B. Sun
5MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
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John Danesh
5MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
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Heiko Runz
6Translational Genome Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, USA
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Joseph C. Maranville
7Informatics and Predictive Sciences, Celgene Corporation, 200 Cambridgepark Dr, Cambridge, MA, USA
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Hannah M. Martin
8School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3FF, UK
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James Yarmolinsky
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Charles Laurin
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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Michael V. Holmes
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
9Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK
10Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
11National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
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Jimmy Liu
6Translational Genome Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, USA
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Karol Estrada
6Translational Genome Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, USA
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Rita Santos
3GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
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Linda McCarthy
3GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
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Dawn Waterworth
2Genetics, GlaxoSmithKline, Collegeville, PA, USA
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Matthew R. Nelson
2Genetics, GlaxoSmithKline, Collegeville, PA, USA
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Gibran Hemani
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
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George Davey Smith
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
12NIHR Bristol Biomedical Research Centre, Bristol, UK
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Adam S. Butterworth
5MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
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Robert A. Scott
3GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
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  • For correspondence: epxjz@bristol.ac.uk
Tom R. Gaunt
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
12NIHR Bristol Biomedical Research Centre, Bristol, UK
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  • For correspondence: epxjz@bristol.ac.uk
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Abstract

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here, we estimated the effects of 1002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium (LD) is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programmes showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of our approach in identifying and prioritising potential therapeutic targets.

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Posted December 06, 2019.
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Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases
Jie Zheng, Valeriia Haberland, Denis Baird, Venexia Walker, Philip Haycock, Mark Hurle, Alex Gutteridge, Pau Erola, Yi Liu, Shan Luo, Jamie Robinson, Tom G. Richardson, James R. Staley, Benjamin Elsworth, Stephen Burgess, Benjamin B. Sun, John Danesh, Heiko Runz, Joseph C. Maranville, Hannah M. Martin, James Yarmolinsky, Charles Laurin, Michael V. Holmes, Jimmy Liu, Karol Estrada, Rita Santos, Linda McCarthy, Dawn Waterworth, Matthew R. Nelson, Gibran Hemani, George Davey Smith, Adam S. Butterworth, Robert A. Scott, Tom R. Gaunt
bioRxiv 627398; doi: https://doi.org/10.1101/627398
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Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases
Jie Zheng, Valeriia Haberland, Denis Baird, Venexia Walker, Philip Haycock, Mark Hurle, Alex Gutteridge, Pau Erola, Yi Liu, Shan Luo, Jamie Robinson, Tom G. Richardson, James R. Staley, Benjamin Elsworth, Stephen Burgess, Benjamin B. Sun, John Danesh, Heiko Runz, Joseph C. Maranville, Hannah M. Martin, James Yarmolinsky, Charles Laurin, Michael V. Holmes, Jimmy Liu, Karol Estrada, Rita Santos, Linda McCarthy, Dawn Waterworth, Matthew R. Nelson, Gibran Hemani, George Davey Smith, Adam S. Butterworth, Robert A. Scott, Tom R. Gaunt
bioRxiv 627398; doi: https://doi.org/10.1101/627398

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