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Genomic atlas of the human plasma proteome

by Kamat, Mihir A. , Paige, Ellie , Fox, Caroline S. , Plenge, Robert M. , Burgess, Stephen , Bradley, John R. , Wood, Angela M. , Morrell, Nicholas W. , Bansal, Narinder , Wilcox, Sheri K. , Chi, An , Runz, Heiko , Janjic, Nebojsa , Staley, James R. , Danesh, John , Jiang, Tao , Paul, Dirk S. , Butterworth, Adam S. , Oliver-Williams, Clare , Sun, Benjamin B. , Todd, John A. , Stacey, David , Maranville, Joseph C. , Zimmerman, Erik S. , Roberts, David J. , Peters, James E. , Spain, Sarah L. , Surendran, Praveen , Suhre, Karsten , Blackshaw, James , Ouwehand, Willem H. , Prins, Bram P. , Soranzo, Nicole

in 45/43 / 631/114/2164 / 631/154/556 / 631/208/199 / 631/208/480 / 631/250/38 / Acids / alpha 1-Antitrypsin - genetics / Architecture / Bioinformatics / Biological activity / Biological markers / Biomarkers / Blood & organ donations / Blood donation / Blood donors / Blood plasma / Blood proteins / Blood Proteins - genetics / Cardiovascular disease / Disease susceptibility / Drug development / Drugs / Female / Gene expression / Gene mapping / Genes / Genetic analysis / Genetic diversity / Genetic factors / Genomes / Genomics / Hepatocyte Growth Factor - genetics / Humanities and Social Sciences / Humans / Inflammatory Bowel Diseases - genetics / Integrated approach / Male / Methods / multidisciplinary / Mutation, Missense - genetics / Myeloblastin - genetics / Physiological aspects / Plasma proteins / Positive Regulatory Domain I-Binding Factor 1 - genetics / Proteins / Proteome - genetics / Proteomes / Proteomics / Proto-Oncogene Proteins - genetics / Quantitative genetics / Quantitative trait loci / Quantitative Trait Loci - genetics / Respiratory system agents / Science / Science (multidisciplinary) / Therapeutic applications / Vasculitis - genetics

2018

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Journal Article

Genomic atlas of the human plasma proteome

Kamat, Mihir A.,

Paige, Ellie,

Fox, Caroline S.,

Plenge, Robert M.,

Burgess, Stephen,

Bradley, John R.,

Wood, Angela M.,

Morrell, Nicholas W.,

Bansal, Narinder,

Wilcox, Sheri K.,

Chi, An,

Runz, Heiko,

Janjic, Nebojsa,

Staley, James R.,

Danesh, John,

Jiang, Tao,

Paul, Dirk S.,

Butterworth, Adam S.,

Oliver-Williams, Clare,

Sun, Benjamin B.,

Todd, John A.,

Stacey, David,

Maranville, Joseph C.,

Zimmerman, Erik S.,

Roberts, David J.,

Peters, James E.,

Spain, Sarah L.,

Surendran, Praveen,

Suhre, Karsten,

Blackshaw, James,

Ouwehand, Willem H.,

Prins, Bram P.,

Soranzo, Nicole

2018

Overview

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development. A genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets.

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Publisher

Nature Publishing Group UK,Nature Publishing Group

Subject

/ Acids