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The UK Biobank Pharma Proteomics Project (UKB-PPP), backed by 13 biopharmaceutical companies, is among the largest and most important biomedical research initiatives run to date. This pioneering endeavor, utilizing the Olink® Explore proteomics platform, has yielded an extensive dataset encompassing nearly 3,000 proteins measured in over 54,000 individuals from the well-characterized UK Biobank. This openly accessible resource serves as a cornerstone for modern biomarker-driven research, promising to accelerate our understanding of human disease, expedite drug development, and catalyze breakthroughs in precision medicine.
In late 2023, the UKB-PPP consortium reported the first outcomes from this project in two landmark articles published in the same issue of Nature (Volume 622 Issue 7982, 12 October 2023). These publications outline a unique, open-access data resource for scientists. Importantly, the articles also present initial findings from the data clearly demonstrating the power of combining genomic and proteomic analysis at this unprecedented scale.
The first article outlines the outcomes of a GWAS-based proteogenomic analysis, identifying thousands of genetic associations with protein expression levels (known as protein quantitative trait loci, pQTLs). These give unique insights into the genetic regulation of proteins and bring genomics closer to phenotype. Over 14,000 pQTLs were identified, 81% of which were novel. Approximately 83% of measured proteins had at least one pQTL with around 67% of these cis-associations, where the genetic variant was closely located to the protein-coding gene. These can be used in Mendelian randomization (MR) analyses to assess causal associations of proteins to phenotypes, an immensely powerful tool to identify robust new drug targets. Moreover, the high number of cis-pQTLs identified provides genetic corroboration of the specificity of the Olink assays. Many trans-pQTLs were also discovered, identifying novel biological pathways and interactions that can accelerate drug discovery, exemplified by new data showing the effects of the ABO blood group on gastrointestinal protein expression and how it may be perturbed in gastrointestinal diseases.
“The study constructs an updated genetic atlas of the plasma proteome, reveals novel biological insights into prevalent illnesses, and provides the scientific community with an open-access, population-scale proteomics resource.”
Sun et al. (2023) Plasma proteomic associations with genetics and health in the UK Biobank. Nature, DOI: 10.1038/s41586-023-06592-6
The second article, primarily authored by AstraZeneca consortium members, delved into the genetic associations of rare protein-coding variants using an EXWAS approach. This revealed over 151,000 genotype-protein associations, 4,400 of which were rare variant pQTLs. Strikingly, 76 % of the rare pQTLs identified by variant-level ExWAS were undetected in a GWAS analysis of the same cohort, showing the significant contribution of rare coding sequence genetic variants. Many novel protein-protein interactions were identified, providing insights into allelic series via multiple rare pQTLs in the same gene (e.g., IL-18) and novel biomarker discoveries, such as six proteins linked to a splice variant pQTL in the HSD17B13 gene that protects against chronic liver diseases. The study illustrates the key role of rare variants in protein regulation and biological outcomes, as well as emphasizing the need for even larger studies to increase the detection power for rarer pQTLs.
“We highlighted several examples of how this protein-coding pQTL atlas can address drug discovery and clinical pipeline challenges.”
Dhindsa et al. (2023) Rare variant associations with plasma protein levels in the UK Biobank. Nature, DOI: 10.1038/s41586-023-06547-x
These and subsequent discoveries from scientists utilizing the UKB-PPP dataset show the immense potential for large-scale proteogenomic analysis of population cohorts to transform the next phase of biomedical research. Olink Explore provided the rapid throughput, high data quality, and analytical performance required to complete this remarkable and ambitious project.
Learn more in our eBook, Empowering Genomics with High-Throughput Proteomics. Download here: go.olink.com/egwp-ebook
