Rare variant associations with plasma protein levels in the UK Biobank


In the UK Biobank Pharma Proteomics Project (UKB-PPP), 13 biopharmaceutical companies generated new proteomic data from accessing the UK Biobank. Using the Olink® Explore platform, they measured around 3,000 proteins covering all major biological pathways  in more than 54,000 UKB participant samples. Members of the UKB-PPP consortium from AstraZeneca have reported on a study focused on the genetic associations of rare proteincoding variants with protein expression and phenotypes, using an exome-wide association study (ExWAS) approach


Over 151,000 significant genotype-protein associations were identified, 5,400 of which corresponded to rare variants (minor allele frequency <0.1%) . Variant-level analysis revealed over 4,400 rare protein quantitative trait loci (pQTLs), while aggregated gene-level analysis identified ~2,000 gene-protein associations. Comparisons showed that 76 % of the rare pQTLs identified by variant-level ExWAS were undetected in the GWAS analysis of the same cohort, showing the specific contribution of rare coding sequence genetic variants.

The utility of rare variant analysis was demonstrated by the identification of both known and novel protein-protein interactions, insights into allelic series via multiple rare pQTLs in the same gene (e.g., IL-18) and novel biomarker discovery, such as 6 proteins linked to a splice variant pQTL in the HSD17B13 gene, known to protect against chronic liver diseases 

This study illustrates the vital role of rare variants in plasma protein level variation and biological outcomes, as well as emphasizing the need for even larger studies to increase  the detection power for rarer pQTLs. The authors also pointed to how this approach could address several drug discovery & development challenges, such as safety assessments and drug repurposing opportunities. 



Dhindsa et al. (2023) Rare variant associations with plasma protein levels in the UK Biobank. Nature, DOI: 10.1038/s41586-023-06547-x

We highlighted several examples of how this protein-coding pQTL atlas can address drug discovery and clinical pipeline challenges. We anticipate that this resource will provide novel insights into protein regulatory networks, upstream trans regulators of target genes whose inhibition could increase target protein levels, target safety assessments and drug repositioning opportunities

Dhindsa et al. (2023)

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