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

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 g...

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Autores principales: Gudjonsson, Alexander, Gudmundsdottir, Valborg, Axelsson, Gisli T., Gudmundsson, Elias F., Jonsson, Brynjolfur G., Launer, Lenore J., Lamb, John R., Jennings, Lori L., Aspelund, Thor, Emilsson, Valur, Gudnason, Vilmundur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789779/
https://www.ncbi.nlm.nih.gov/pubmed/35078996
http://dx.doi.org/10.1038/s41467-021-27850-z
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author Gudjonsson, Alexander
Gudmundsdottir, Valborg
Axelsson, Gisli T.
Gudmundsson, Elias F.
Jonsson, Brynjolfur G.
Launer, Lenore J.
Lamb, John R.
Jennings, Lori L.
Aspelund, Thor
Emilsson, Valur
Gudnason, Vilmundur
author_facet Gudjonsson, Alexander
Gudmundsdottir, Valborg
Axelsson, Gisli T.
Gudmundsson, Elias F.
Jonsson, Brynjolfur G.
Launer, Lenore J.
Lamb, John R.
Jennings, Lori L.
Aspelund, Thor
Emilsson, Valur
Gudnason, Vilmundur
author_sort Gudjonsson, Alexander
collection PubMed
description 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 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% 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.
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spelling pubmed-87897792022-02-07 A genome-wide association study of serum proteins reveals shared loci with common diseases Gudjonsson, Alexander Gudmundsdottir, Valborg Axelsson, Gisli T. Gudmundsson, Elias F. Jonsson, Brynjolfur G. Launer, Lenore J. Lamb, John R. Jennings, Lori L. Aspelund, Thor Emilsson, Valur Gudnason, Vilmundur Nat Commun Article 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 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% 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. Nature Publishing Group UK 2022-01-25 /pmc/articles/PMC8789779/ /pubmed/35078996 http://dx.doi.org/10.1038/s41467-021-27850-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gudjonsson, Alexander
Gudmundsdottir, Valborg
Axelsson, Gisli T.
Gudmundsson, Elias F.
Jonsson, Brynjolfur G.
Launer, Lenore J.
Lamb, John R.
Jennings, Lori L.
Aspelund, Thor
Emilsson, Valur
Gudnason, Vilmundur
A genome-wide association study of serum proteins reveals shared loci with common diseases
title A genome-wide association study of serum proteins reveals shared loci with common diseases
title_full A genome-wide association study of serum proteins reveals shared loci with common diseases
title_fullStr A genome-wide association study of serum proteins reveals shared loci with common diseases
title_full_unstemmed A genome-wide association study of serum proteins reveals shared loci with common diseases
title_short A genome-wide association study of serum proteins reveals shared loci with common diseases
title_sort genome-wide association study of serum proteins reveals shared loci with common diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789779/
https://www.ncbi.nlm.nih.gov/pubmed/35078996
http://dx.doi.org/10.1038/s41467-021-27850-z
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