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

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 Me...

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Vydané v:	Nature genetics Ročník 52; číslo 10; s. 1122 - 1131
Hlavní autori:	Zheng, Jie, Haberland, Valeriia, Baird, Denis, Walker, Venexia, Haycock, Philip C., Hurle, Mark R., Gutteridge, Alex, Erola, Pau, Liu, Yi, Luo, Shan, Robinson, Jamie, Richardson, Tom G., Staley, James R., Elsworth, Benjamin, Burgess, Stephen, Sun, Benjamin B., Danesh, John, Runz, Heiko, Maranville, Joseph C., Martin, Hannah M., Yarmolinsky, James, Laurin, Charles, Holmes, Michael V., Liu, Jimmy Z., Estrada, Karol, Santos, Rita, McCarthy, Linda, Waterworth, Dawn, Nelson, Matthew R., Smith, George Davey, Butterworth, Adam S., Hemani, Gibran, Scott, Robert A., Gaunt, Tom R.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.10.2020 Nature Publishing Group
Predmet:	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
ISSN:	1061-4036, 1546-1718, 1546-1718
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Proteome MR writing group
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-020-0682-6