Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease
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Abstract
Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
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For the common variant pQTL analysis power calculations with n = 500, the study assumed linear regression with an additive genetic model with no gene-gene interactions using genpwr, following the strategy previously used by Yao et al.
“For the common variant pQTL analysis power calculations with n = 500, we assumed linear regression with an additive genetic model with no gene–gene interactions using genpwr (version 1.0.4) R package33, following the strategy previously used by Yao et al.34.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as Yao et al. [34]
CSF Siglec-9, plasma sICAM-1, and brain PPAC have been replicated in other studies using a different proteomic approach, indicating these findings may not be driven by platform.
“CSF Siglec-9, plasma sICAM-1, and brain PPAC have been replicated in other studies16,29,31,32 using a different proteomic approach, which indicates that these findings may not be driven by platform.”
From Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders (2021) · cites this paper as [31]
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Genomic atlas of the human plasma proteome
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GDF15: a hormone conveying somatic distress to the brain
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- Authors
- Yao, C., Chen, G., Song, C., Keefe, J., Mendelson, M., Huan, T., Sun, B. B., Laser, A., Maranville, J. C., Wu, H., Ho, J. E., Courchesne, P., Lyass, A., Larson, M. G., Gieger, C., Graumann, J., Johnson, A. D., Danesh, J., Runz, H., Hwang, S.-J., Liu, C., Butterworth, A. S., Suhre, K., & Levy, D.
- Affiliations
- National Institutes of Health (US)
- Uppsala University (SE)
- Boston Children's Hospital (US)
- University of Cambridge (GB)
- Helmholtz Munich (DE)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Wentworth Institute of Technology (US)
- Massachusetts General Hospital (US)
- Boston University (US)
- Max Planck Institute for Heart and Lung Research (DE)
- Weill Cornell Medical College in Qatar (QA)
- Corresponding author
- Levy, Daniel
- ORCID
- Yao, Chen
- Song, Ci
- Keefe, Joshua
- Mendelson, Michael
- Huan, Tianxiao
- Sun, Benjamin B.
- Maranville, Joseph C.
- Ho, Jennifer E.
- Courchesne, Paul
- Lyass, Asya
- Larson, Martin G.
- Gieger, Christian
- Graumann, Johannes
- Johnson, Andrew D.
- Danesh, John
- Runz, Heiko
- Hwang, Shih-Jen
- Liu, Chunyu
- Butterworth, Adam S.
- Suhre, Karsten
- Levy, Daniel
- Venue
- Nature Communications
- Published
- 2018-08-15
- Volume
- 9
- Issue
- 1
- Pages
- 3268-3268
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6093935
- OpenAlex
- W2886245587
- Cited by
- 431
- References
- 101
- Citations by year
- 2026: 41 · 2025: 69 · 2024: 90 · 2023: 59 · 2022: 51 · 2021: 45 · 2020: 53 · 2019: 18 · 2018: 4 · 2017: 1
- FWCI
- 18.86
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-09-18)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- U.S. Department of Health and Human Services (N01-HC-25195)
- Massachusetts General Hospital
- Qatar Foundation
- NHS Blood and Transplant (11-01-GEN, NIHR BTRU-2014-10024)
- National Institute for Health and Care Research (NF-SI-0617-10113, NF-SI-0512-10165, NIHR BTRU‐2014‐10024, BTRU-2014–10024)
- British Heart Foundation (G0800270, SP/09/002, RG/13/13/30194)
- University of Cambridge
- European Commission (279233)
- Bundesministerium für Bildung und Forschung
- National Institutes of Health (n01hc25195-41-0-1, N01-HC 25195)
- Weill Cornell Medical College
- Weill Cornell Medicine - Qatar
- Medical Research Council (SP/09/002, MR/L003120/1, G0800270)
- Helmholtz Zentrum München
- NIHR Cambridge Biomedical Research Centre (BTRU-2014-10024)
- National Heart, Lung, and Blood Institute (HC25195, K99HL136875, N01‐HC25195, N01-HC, K23HL116780, N01-HC-025195)
- FP7 Ideas: European Research Council (268834)
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- circulating proteins, cardiovascular disease, coronary disease, Mendelian randomization, Framingham Heart Study, genetic risk variants
- MeSH terms
- Adult, Blood Proteins, Cardiovascular Diseases, Chromosome Mapping, Female, Humans, Male, Middle Aged, Risk Factors, Signal Transduction, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, Quantitative Trait Loci, Genome-Wide Association Study
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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