Genetic Associations with Ratios Between Protein Levels Detect New PQTLs and Reveal Protein-protein Interactions

Overview

Journal Cell Genom

Date 2024 Feb 27

PMID 38412862

Authors

Karsten Suhre

Affiliations

Soon will be listed here.

Abstract

Protein quantitative trait loci (pQTLs) are an invaluable source of information for drug target development because they provide genetic evidence to support protein function, suggest relationships between cis- and trans-associated proteins, and link proteins to disease endpoints. Using Olink proteomics data for 1,463 proteins measured in over 54,000 samples of the UK Biobank, we identified 4,248 associations with 2,821 ratios between protein levels (rQTLs). rQTLs were 7.6-fold enriched in known protein-protein interactions, suggesting that their ratios reflect biological links between the implicated proteins. Conducting a GWAS on ratios increased the number of discovered genetic signals by 24.7%. The approach can identify novel loci of clinical relevance, support causal gene identification, and reveal complex networks of interacting proteins. Taken together, our study adds significant value to the genetic insights that can be derived from the UKB proteomics data and motivates the wider use of ratios in large-scale GWAS.

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References

Suhre K, Shin S, Petersen A, Mohney R, Meredith D, Wagele B . Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011; 477(7362):54-60. PMC: 3832838. DOI: 10.1038/nature10354. View

Liu J, van Sommeren S, Huang H, Ng S, Alberts R, Takahashi A . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015; 47(9):979-986. PMC: 4881818. DOI: 10.1038/ng.3359. View

Lu Z, Hunter T . Degradation of activated protein kinases by ubiquitination. Annu Rev Biochem. 2009; 78:435-75. PMC: 2776765. DOI: 10.1146/annurev.biochem.013008.092711. View

Hopkins A . Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008; 4(11):682-90. DOI: 10.1038/nchembio.118. View

Folkersen L, Gustafsson S, Wang Q, Hansen D, Hedman A, Schork A . Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metab. 2020; 2(10):1135-1148. PMC: 7611474. DOI: 10.1038/s42255-020-00287-2. View

Lee J, Kim L, Choi J . Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases. Front Immunol. 2018; 9:2747. PMC: 6277705. DOI: 10.3389/fimmu.2018.02747. View

Emilsson V, Ilkov M, Lamb J, Finkel N, Gudmundsson E, Pitts R . Co-regulatory networks of human serum proteins link genetics to disease. Science. 2018; 361(6404):769-773. PMC: 6190714. DOI: 10.1126/science.aaq1327. View

Hollingworth P, Sweet R, Sims R, Harold D, Russo G, Abraham R . Genome-wide association study of Alzheimer's disease with psychotic symptoms. Mol Psychiatry. 2011; 17(12):1316-27. PMC: 3272435. DOI: 10.1038/mp.2011.125. View

Dhillon B, Smith M, Baghela A, Lee A, Hancock R . Systems Biology Approaches to Understanding the Human Immune System. Front Immunol. 2020; 11:1683. PMC: 7406790. DOI: 10.3389/fimmu.2020.01683. View

10.

Krumsiek J, Suhre K, Illig T, Adamski J, Theis F . Gaussian graphical modeling reconstructs pathway reactions from high-throughput metabolomics data. BMC Syst Biol. 2011; 5:21. PMC: 3224437. DOI: 10.1186/1752-0509-5-21. View

11.

Boughton A, Welch R, Flickinger M, VandeHaar P, Taliun D, Abecasis G . LocusZoom.js: interactive and embeddable visualization of genetic association study results. Bioinformatics. 2021; 37(18):3017-3018. PMC: 8479674. DOI: 10.1093/bioinformatics/btab186. View

12.

Nibbs R, Graham G . Immune regulation by atypical chemokine receptors. Nat Rev Immunol. 2013; 13(11):815-29. DOI: 10.1038/nri3544. View

13.

Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C . A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2009; 42(2):137-41. PMC: 3773904. DOI: 10.1038/ng.507. View

14.

Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S . The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinformatics. 2016; 54:1.30.1-1.30.33. DOI: 10.1002/cpbi.5. View

15.

Wallace C . A more accurate method for colocalisation analysis allowing for multiple causal variants. PLoS Genet. 2021; 17(9):e1009440. PMC: 8504726. DOI: 10.1371/journal.pgen.1009440. View

16.

Shin S, Fauman E, Petersen A, Krumsiek J, Santos R, Huang J . An atlas of genetic influences on human blood metabolites. Nat Genet. 2014; 46(6):543-550. PMC: 4064254. DOI: 10.1038/ng.2982. View

17.

Sun B, Maranville J, Peters J, Stacey D, Staley J, Blackshaw J . Genomic atlas of the human plasma proteome. Nature. 2018; 558(7708):73-79. PMC: 6697541. DOI: 10.1038/s41586-018-0175-2. View

18.

Sheils T, Mathias S, Kelleher K, Siramshetty V, Nguyen D, Bologa C . TCRD and Pharos 2021: mining the human proteome for disease biology. Nucleic Acids Res. 2020; 49(D1):D1334-D1346. PMC: 7778974. DOI: 10.1093/nar/gkaa993. View

19.

Lagace T, Curtis D, Garuti R, McNutt M, Park S, Prather H . Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 2006; 116(11):2995-3005. PMC: 1626117. DOI: 10.1172/JCI29383. View

20.

Wang Q, Zhou Y, Jackson L, Johnson S, Chow C, Evers B . Nuclear factor of activated T cells (NFAT) signaling regulates PTEN expression and intestinal cell differentiation. Mol Biol Cell. 2010; 22(3):412-20. PMC: 3031470. DOI: 10.1091/mbc.E10-07-0598. View