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A genome-wide association study of serum proteins reveals shared loci with common diseases

Alexander Gudjonsson, View ORCID ProfileValborg Gudmundsdottir, View ORCID ProfileGisli T Axelsson, View ORCID ProfileElias F Gudmundsson, Brynjolfur G Jonsson, View ORCID ProfileLenore J Launer, John R Lamb, Lori L Jennings, View ORCID ProfileThor Aspelund, View ORCID ProfileValur Emilsson, View ORCID ProfileVilmundur Gudnason
doi: https://doi.org/10.1101/2021.07.02.450858
Alexander Gudjonsson
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
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Valborg Gudmundsdottir
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
2Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
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Gisli T Axelsson
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
2Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
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Elias F Gudmundsson
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
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  • ORCID record for Elias F Gudmundsson
Brynjolfur G Jonsson
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
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Lenore J Launer
3Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD 20892-9205, USA
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John R Lamb
4GNF Novartis, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
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Lori L Jennings
5Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA
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Thor Aspelund
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
2Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
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Valur Emilsson
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
2Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
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Vilmundur Gudnason
1Icelandic Heart Association, Holtasmari 1, 201 Kopavogur, Iceland
2Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
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  • For correspondence: v.gudnason@hjarta.is
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Abstract

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,113 independent associations between genetic variants and 2,099 serum proteins, of which 37% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein’s genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

Competing Interest Statement

The study was supported by the Novartis Institute for Biomedical Research, and protein measurements for the AGES-Reykjavik cohort were performed at SomaLogic. J.R.L. and L.L.J. are employees and stockholders of Novartis. All other authors have no conflict of interests to declare.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted July 04, 2021.
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A genome-wide association study of serum proteins reveals shared loci with common diseases
Alexander Gudjonsson, Valborg Gudmundsdottir, Gisli T Axelsson, Elias F Gudmundsson, Brynjolfur G Jonsson, Lenore J Launer, John R Lamb, Lori L Jennings, Thor Aspelund, Valur Emilsson, Vilmundur Gudnason
bioRxiv 2021.07.02.450858; doi: https://doi.org/10.1101/2021.07.02.450858
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A genome-wide association study of serum proteins reveals shared loci with common diseases
Alexander Gudjonsson, Valborg Gudmundsdottir, Gisli T Axelsson, Elias F Gudmundsson, Brynjolfur G Jonsson, Lenore J Launer, John R Lamb, Lori L Jennings, Thor Aspelund, Valur Emilsson, Vilmundur Gudnason
bioRxiv 2021.07.02.450858; doi: https://doi.org/10.1101/2021.07.02.450858

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