Connecting genetic risk to disease end points through the human blood plasma proteome

Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex...

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Published in:Nature communications Vol. 8; no. 1; pp. 14357 - 14
Main Authors: Suhre, Karsten, Arnold, Matthias, Bhagwat, Aditya Mukund, Cotton, Richard J., Engelke, Rudolf, Raffler, Johannes, Sarwath, Hina, Thareja, Gaurav, Wahl, Annika, DeLisle, Robert Kirk, Gold, Larry, Pezer, Marija, Lauc, Gordan, El-Din Selim, Mohammed A., Mook-Kanamori, Dennis O., Al-Dous, Eman K., Mohamoud, Yasmin A., Malek, Joel, Strauch, Konstantin, Grallert, Harald, Peters, Annette, Kastenmüller, Gabi, Gieger, Christian, Graumann, Johannes
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.02.2017
Nature Publishing Group
Nature Portfolio
Subjects:
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Alleles
Alzheimer's disease
Blood Proteins - metabolism
Cardiovascular disease
Complement System Proteins - metabolism
Diabetes
Drug Delivery Systems
Education
Endpoint Determination
Environmental health
Epidemiology
Gene Regulatory Networks
Genetic Predisposition to Disease
Genetic variance
Genetic Variation
Genome, Human
Genome-Wide Association Study
Genomes
Glycoproteins - metabolism
Health risk assessment
Heme - metabolism
Humanities and Social Sciences
Humans
Immunoassay
Metabolites
Molecular Sequence Annotation
multidisciplinary
Pharmacogenetics
Plasma
Protein Processing, Post-Translational - genetics
Proteins
Proteome - genetics
Proteome - metabolism
Proteomics
Quantitative Trait Loci
Reproducibility of Results
Research centers
Risk Factors
RNA Splicing - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
Science
Science (multidisciplinary)
Scientific imaging
Qatar
Germany
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans . Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications. Individual genetic variation can affect the levels of protein in blood, but detailed data sets linking these two types of data are rare. Here, the authors carry out a genome-wide association study of levels of over a thousand different proteins, and describe many new SNP-protein interactions.
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Present address: Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, Ludwigstr. 43, D-61231 Bad Nauheim, Germany.
These authors contributed equally to this work.
These authors jointly supervised this work.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms14357