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Cited by 107Genetic Associations and EpidemiologyGenomics and Rare DiseasesGenetic Mapping and Diversity in Plants and Animals

Whole-genome sequencing analysis of the cardiometabolic proteome

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Gilly, Arthur, Park, Young-Chan, Png, Grace, Barysenka, Andrei, Fischer, Iris, Bjørnland, Thea, Southam, Lorraine, Suveges, Daniel +6 more·2020·Nature Communications
DOI 10.1038/s41467-020-20079-2PMC PMC7729872

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Abstract

The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations ( P < 7.45 × 10 −11 ) across the allele frequency spectrum, all of which replicate in an independent cohort ( n = 1605, 18.4 x WGS). We identify for the first time replicating evidence for rare-variant cis -acting protein quantitative trait loci for five genes, involving both coding and noncoding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets.

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Cited by

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Authors
Gilly, A., Park, Y.-C., Png, G., Barysenka, A., Fischer, I., Bjørnland, T., Southam, L., Suveges, D., Neumeyer, S., Rayner, N. W., Tsafantakis, E., Karaleftheri, M., Dedoussis, G., & Zeggini, E.
Affiliations
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • Helmholtz Munich (DE)
  • Norwegian University of Science and Technology (NO)
  • Centre for Human Genetics (GB)
  • Harokopio University of Athens (GR)
Corresponding author
Zeggini, Eleftheria
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-12-10
Volume
11
Issue
1
Pages
6336-6336
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20079-2
PMC
PMC7729872
OpenAlex
W3113104574
Cited by
107
References
4
Citations by year
2026: 11 · 2025: 28 · 2024: 35 · 2023: 17 · 2022: 8 · 2021: 5 · 2020: 3
FWCI
4.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
  • Site cant be reached (submittedVersion)
  • Site cant be reached (submittedVersion, cc-by)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
Wellcome Trust (098051)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
circulating protein biomarkers, polygenic risk score, protein quantitative trait loci, drug discovery targets
MeSH terms
Whole Genome Sequencing, Gene Expression Regulation, Humans, Myocardium, Risk Factors, Genetic Predisposition to Disease, Multifactorial Inheritance, Proteome, Quantitative Trait Loci, Gene Regulatory Networks

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