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

Jie Zheng; Valeriia Haberland; Denis A Baird; Venexia M Walker; Philip C Haycock; Mark R.  Hurle; Alex  Gutteridge; Pau Erola; Yi Liu; Shan Luo; Jamie W Robinson; Tom G Richardson; James R Staley; Benjamin L Elsworth; Stephen  Burgess; Benjamin B Sun; John  Danesh; Heiko Runz; Joseph C. Maranville; Hannah M Martin; James Yarmolinsky; Charles A Laurin; Michael V Holmes; Jimmy Z Liu; Karol Estrada; Rita  Santos; Linda  McCarthy; Dawn  Waterworth; Matthew R.  Nelson; George Davey Smith; Adam S  Butterworth; Gibran Hemani; Robert A.  Scott; Tom R Gaunt

doi:10.1038/s41588-020-0682-6

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

Jie Zheng^*, Valeriia Haberland, Denis A Baird, Venexia M Walker, Philip C Haycock, Mark R. Hurle, Alex Gutteridge, Pau Erola, Yi Liu, Shan Luo, Jamie W Robinson, Tom G Richardson, James R Staley, Benjamin L Elsworth, Stephen Burgess, Benjamin B Sun, John Danesh , Heiko Runz, Joseph C. Maranville, Hannah M MartinJames Yarmolinsky, Charles A Laurin, Michael V Holmes, Jimmy Z Liu, Karol Estrada, Rita Santos, Linda McCarthy, Dawn Waterworth, Matthew R. Nelson, George Davey Smith, Adam S Butterworth , Gibran Hemani, Robert A. Scott^*, Tom R Gaunt^*

^*Corresponding author for this work

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

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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 1,002 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 is widespread in naïve 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 (https://www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

Original language	English
Pages (from-to)	1122–1131
Number of pages	15
Journal	Nature Genetics
Volume	52
DOIs	https://doi.org/10.1038/s41588-020-0682-6
Publication status	Published - 7 Sept 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Drug discovery
Genetics
High-throughput screening
Proteomics

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10.1038/s41588-020-0682-6

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https://www.repository.cam.ac.uk/handle/1810/306909

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Professor Tom R Gaunt
- Tom.Gauntbristol.acuk
- Bristol Medical School (PHS) - Professor of Health and Biomedical Informatics and MRC Investigator
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit - Programme lead
Person: Academic , Member
Professor Gibran Hemani
- g.hemanibristol.acuk
- Bristol Medical School (PHS) - Professor in Statistical Genetics
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
Person: Academic , Member

Cite this

Zheng, J., Haberland, V., Baird, D. A., Walker, V. M., Haycock, P. C., Hurle, M. R., Gutteridge, A., Erola, P., Liu, Y., Luo, S., Robinson, J. W., Richardson, T. G., Staley, J. R., Elsworth, B. L., Burgess, S., Sun, B. B., Danesh , J., Runz, H., Maranville, J. C., ... Gaunt, T. R. (2020). Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases. Nature Genetics, 52, 1122–1131 . https://doi.org/10.1038/s41588-020-0682-6

@article{ffb82be5d80a425eba6f7202ad0d8bda,

title = "Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases",

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 1,002 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 is widespread in na{\"i}ve 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 (https://www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.",

keywords = "Drug discovery, Genetics, High-throughput screening, Proteomics",

author = "Jie Zheng and Valeriia Haberland and Baird, \{Denis A\} and Walker, \{Venexia M\} and Haycock, \{Philip C\} and Hurle, \{Mark R.\} and Alex Gutteridge and Pau Erola and Yi Liu and Shan Luo and Robinson, \{Jamie W\} and Richardson, \{Tom G\} and Staley, \{James R\} and Elsworth, \{Benjamin L\} and Stephen Burgess and Sun, \{Benjamin B\} and John Danesh and Heiko Runz and Maranville, \{Joseph C.\} and Martin, \{Hannah M\} and James Yarmolinsky and Laurin, \{Charles A\} and Holmes, \{Michael V\} and Liu, \{Jimmy Z\} and Karol Estrada and Rita Santos and Linda McCarthy and Dawn Waterworth and Nelson, \{Matthew R.\} and \{Davey Smith\}, George and Butterworth, \{Adam S\} and Gibran Hemani and Scott, \{Robert A.\} and Gaunt, \{Tom R\}",

year = "2020",

month = sep,

day = "7",

doi = "10.1038/s41588-020-0682-6",

language = "English",

volume = "52",

pages = "1122–1131 ",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

}

Zheng, J, Haberland, V, Baird, DA, Walker, VM , Haycock, PC, Hurle, MR, Gutteridge, A, Erola, P, Liu, Y, Luo, S, Robinson, JW, Richardson, TG, Staley, JR, Elsworth, BL, Burgess, S, Sun, BB, Danesh , J, Runz, H, Maranville, JC, Martin, HM, Yarmolinsky, J, Laurin, CA, Holmes, MV, Liu, JZ, Estrada, K, Santos, R, McCarthy, L, Waterworth, D, Nelson, MR, Davey Smith, G, Butterworth , AS, Hemani, G, Scott, RA & Gaunt, TR 2020, 'Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases', Nature Genetics, vol. 52, pp. 1122–1131 . https://doi.org/10.1038/s41588-020-0682-6

TY - JOUR

T1 - Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

AU - Zheng, Jie

AU - Haberland, Valeriia

AU - Baird, Denis A

AU - Walker, Venexia M

AU - Haycock, Philip C

AU - Hurle, Mark R.

AU - Gutteridge, Alex

AU - Erola, Pau

AU - Liu, Yi

AU - Luo, Shan

AU - Robinson, Jamie W

AU - Richardson, Tom G

AU - Staley, James R

AU - Elsworth, Benjamin L

AU - Burgess, Stephen

AU - Sun, Benjamin B

AU - Danesh , John

AU - Runz, Heiko

AU - Maranville, Joseph C.

AU - Martin, Hannah M

AU - Yarmolinsky, James

AU - Laurin, Charles A

AU - Holmes, Michael V

AU - Liu, Jimmy Z

AU - Estrada, Karol

AU - Santos, Rita

AU - McCarthy, Linda

AU - Waterworth, Dawn

AU - Nelson, Matthew R.

AU - Davey Smith, George

AU - Butterworth , Adam S

AU - Hemani, Gibran

AU - Scott, Robert A.

AU - Gaunt, Tom R

PY - 2020/9/7

Y1 - 2020/9/7

N2 - 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 1,002 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 is widespread in naïve 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 (https://www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

AB - 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 1,002 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 is widespread in naïve 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 (https://www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

KW - Drug discovery

KW - Genetics

KW - High-throughput screening

KW - Proteomics

U2 - 10.1038/s41588-020-0682-6

DO - 10.1038/s41588-020-0682-6

M3 - Article (Academic Journal)

C2 - 32895551

SN - 1061-4036

VL - 52

SP - 1122

EP - 1131

JO - Nature Genetics

JF - Nature Genetics

ER -

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

Abstract

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Professor Tom R Gaunt

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