Phenome-wide Mendelian Randomization Mapping the Influence of the Plasma Proteome on Complex Diseases

Overview

Journal Nat Genet

Specialty Genetics

Date 2020 Sep 8

PMID 32895551

Citations 254

Authors

Jie Zheng

Valeriia Haberland

Denis Baird

Venexia Walker

Philip C Haycock

Mark R 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 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

Affiliations

Soon will be listed here.

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.

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