Connecting genetic risk to disease endpoints through the human blood plasma proteome

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

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Published inbioRxiv
Main Authors Suhre, Karsten, Arnold, Matthias, Bhagwat, Aditya, Cotton, Richard J, Engelke, Rudolf, Laser, Annika, Raffler, Johannes, Sarwath, Hina, Thareja, Gaurav, Robert Kirk Delisle, 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, Kastenmuller, Gabi, Gieger, Christian, Graumann, Johannes
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 09.11.2016
Subjects
Alzheimer's disease
Aptamers
Autoimmune diseases
Cardiovascular diseases
Gene mapping
Genome-wide association studies
Genomes
Health risk assessment
Neurodegenerative diseases
Peptide mapping
Phenotypes
Proteins
Proteomics
Single-nucleotide polymorphism
Therapeutic applications
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Summary:Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence for mapping disease associations and translating them into clinical applications. However, although hundreds of genetic risk variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits across multiple chromosome locations are key in establishing functional links between GWAS-identified risk-variants and disease endpoints. Here, we describe a GWAS performed with a highly multiplexed aptamer-based affinity proteomics platform. We quantified associations between protein level changes and gene variants in a German cohort and replicated this GWAS in an Arab/Asian cohort. We identified many independent, SNP-protein associations, which represent novel, inter-chromosomal links, related to autoimmune disorders, Alzheimer's disease, cardiovascular disease, cancer, and many other disease endpoints. We integrated this information into a genome-proteome network, and created an interactive web-tool for interrogations. Our results provide a basis for new approaches to pharmaceutical and diagnostic applications.
DOI:10.1101/086793