title: Connecting genetic risk to disease end points through the human blood plasma proteome.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Karsten
authors.identifier: 0000-0001-9638-3912
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Matthias
authors.identifier: 0000-0002-4666-0923
authors.initials: M
authors.lastname: Arnold
authors.affiliation: Proteomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Aditya Mukund
authors.initials: AM
authors.lastname: Bhagwat
authors.affiliation: Proteomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cotton
authors.affiliation: Proteomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Engelke
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Raffler
authors.affiliation: Proteomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Hina
authors.initials: H
authors.lastname: Sarwath
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Thareja
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wahl
authors.affiliation: SomaLogic, 2945 Wilderness Pl, Boulder, Colorado 80301, USA.
authors.forename: Robert Kirk
authors.initials: RK
authors.lastname: DeLisle
authors.affiliation: SomaLogic, 2945 Wilderness Pl, Boulder, Colorado 80301, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Gold
authors.affiliation: Genos Ltd, Glycoscience Research Laboratory, Hondlova 2/11, 10000 Zagreb, Croatia.
authors.forename: Marija
authors.identifier: 0000-0002-6480-1427
authors.initials: M
authors.lastname: Pezer
authors.affiliation: Genos Ltd, Glycoscience Research Laboratory, Hondlova 2/11, 10000 Zagreb, Croatia.
authors.forename: Gordan
authors.initials: G
authors.lastname: Lauc
authors.affiliation: Department of Dermatology, Hamad Medical Corporation, PO Box 3050 Doha, Qatar.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: El-Din Selim
authors.affiliation: Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Mook-Kanamori
authors.affiliation: Genomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar.
authors.forename: Eman K
authors.initials: EK
authors.lastname: Al-Dous
authors.affiliation: Genomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar.
authors.forename: Yasmin A
authors.initials: YA
authors.lastname: Mohamoud
authors.affiliation: Genomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144, Doha, Qatar.
authors.forename: Joel
authors.initials: J
authors.lastname: Malek
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Marchioninistraße 15, 81377 München, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|German Center for Cardiovascular Disease Research (DZHK), Oudenarder Straße 16, 13347 Berlin, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.|German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Proteomics Core, Weill Cornell Medicine-Qatar, Education City, PO 24144 Doha, Qatar.
authors.forename: Johannes
authors.identifier: 0000-0002-3015-5850
authors.initials: J
authors.lastname: Graumann
mesh_terms: D000483:Alleles; D001798:Blood Proteins / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism; D016503:Drug Delivery Systems; D023381:Endpoint Determination; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006801:Humans; D058977:Molecular Sequence Annotation; D010597:Pharmacogenetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D001798:Blood Proteins; D006023:Glycoproteins; D020543:Proteome; D012333:RNA, Messenger; D006418:Heme; D003165:Complement System Proteins