Journal Article

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

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

2020

Overview

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. Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/43 / 631/114/2163 / 631/154 / 631/208 / 631/337/475 / 82/80 / 96/47 / Agriculture / Alzheimer's disease / Analysis / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Blood proteins / Blood Proteins - genetics / Cancer Research / Causality / Clinical trials / Crohn's disease / Drug development / Gene Function / Gene mapping / Genetic analysis / Genetic aspects / Genetic Predisposition to Disease / Genetics / Genome-Wide Association Study / Genotype & phenotype / Health aspects / Human Genetics / Humans / Linkage disequilibrium / Mapping / Mendelian Randomization Analysis / Phenotype / Phenotypes / Plasma / Polymorphism, Single Nucleotide - genetics / Proteins / Proteome - genetics / Proteomes / Randomization / Risk factors / Therapeutic applications