Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
Open accessAbstract
We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis -instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
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The associations were strongest for significant cis-pQTL variants located nearest to the TSSs of the relevant protein genes.
“In concordance with previous studies4,9,65, there was an inverse relationship between the effect size and MAF (Fig. 2b), and the associations were the strongest for significant cis-pQTL variants located nearest to the TSSs of the relevant protein genes (Fig. 2c).”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [65]
There was an inverse relationship between effect size and MAF.
“In concordance with previous studies4,9,65, there was an inverse relationship between the effect size and MAF (Fig. 2b), and the associations were the strongest for significant cis-pQTL variants located nearest to the TSSs of the relevant protein genes (Fig. 2c).”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [65]
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Plasma proteomic associations with genetics and health in the UK Biobank
Sun, B. B., Chiou, J., Traylor, M., Benner, C., Hsu, Y.-H., Richardson, T. G., Surendran, P., Mahajan, A., Robins, C., Vasquez-Grinnell, S. G., et al. (2023) · Nature · doi:10.1038/s41586-023-06592-6 · Cited by 1,740 · see citing works
Self-citationGenetic determinants of plasma protein levels in the Estonian population
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- Authors
- Macdonald-Dunlop, E., Klarić, L., Folkersen, L., Timmers, P. R. H. J., Gustafsson, S., Zhao, J. H., Eriksson, N., Richmond, A., Enroth, S., Mattsson-Carlgren, N., Zhernakova, D. V., Kalnapenkis, A., Magnusson, M., Wheeler, E., Hwang, S.-J., Chen, Y., Morris, A. P., Prins, B., Võsa, U., Wareham, N. J., Danesh, J., Sundstrom, J., Gigante, B., Baldassarre, D., Strawbridge, R. J., Campbell, H., Gyllensten, U., Yao, C., Zanetti, D., Assimes, T. L., Eriksson, P., Levy, D., Langenberg, C., Smith, J. G., Esko, T., Fu, J., Hansson, O., Johansson, Å., Hayward, C., Wallentin, L., Siegbahn, A., Lind, L., Butterworth, A. S., Michaëlsson, K., Peters, J. E., Mälarstig, A., Joshi, P. K., & Wilson, J. F.
- Affiliations
- University of Edinburgh (GB)
- Western General Hospital (GB)
- Uppsala University (SE)
- University of Cambridge (GB)
- University Medical Center Groningen (NL)
- University of Tartu (EE)
- Lund University (SE)
- National Institutes of Health (US)
- Karolinska Institutet (SE)
- University of Manchester (GB)
- University of Milan (IT)
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Karolinska University Hospital (SE)
- Corresponding author
- Wilson, James F.
- ORCID
- Macdonald-Dunlop, Erin
- Klarić, Lucija
- Folkersen, Lasse
- Timmers, Paul R.H.J.
- Gustafsson, Stefan
- Zhao, Jing Hua
- Eriksson, Niclas
- Richmond, Anne
- Enroth, Stefan
- Zhernakova, Daria V.
- Kalnapenkis, Anette
- Magnusson, Martin
- Wheeler, Eleanor
- Hwang, Shih-Jen
- Chen, Yan
- Morris, Andrew P
- Prins, Bram
- Võsa, Urmo
- Wareham, Nicholas J.
- Danesh, John
- Sundstrom, Johan
- Gigante, Bruna
- Baldassarre, Damiano
- Strawbridge, Rona J.
- Gyllensten, Ulf
- Yao, Chen
- Zanetti, Daniela
- Assimes, Themistocles L.
- Eriksson, Per
- Levy, Daniel
- Langenberg, Claudia
- Smith, J. Gustav
- Esko, Tõnu
- Fu, Jingyuan
- Hansson, Oskar
- Johansson, Åsa
- Hayward, Caroline
- Wallentin, Lars
- Siegbahn, Agneta
- Lind, Lars
- Butterworth, Adam S.
- Michaëlsson, Karl
- Peters, James E.
- Mälarstig, Anders
- Joshi, Peter K.
- Wilson, James F.
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2021-08-05
- OpenAlex
- W3193093890
- Cited by
- 9
- References
- 4
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 4 · 2022: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- medRxiv (acceptedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Biogen
- UK Research and Innovation (MR/S003061/1, MR/R026408/1)
- Research Councils UK (MR/R026408/1)
- Eisai
- Avid Radiopharmaceuticals
- Medical Research Council (MC_UU_12015/1, MR/N013166/1, MR/S003061/1, MR/R026408/1, MC_UU_00007/10, MR/L003120/1)
- 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
- plasma protein levels, protein quantitative trait loci, expression quantitative trait loci, transcription factor binding, genetic architecture, cardiometabolic traits, PCSK9, LDL cholesterol, IL-27, TNFRSF14, Crohn's disease, inflammatory bowel disease, multiple sclerosis, ulcerative colitis, drug repurposing, therapeutic target
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