Influences of rare protein-coding genetic variants on the human plasma proteome in 50,829 UK Biobank participants

Combining human genomics with proteomics is becoming a powerful tool for drug discovery. Associations between genetic variants and protein levels can uncover disease mechanisms, clinical biomarkers, and candidate drug targets. To date, most population-level proteogenomic studies have focused on common alleles through genome-wide association studies (GWAS). Here, we studied the contribution of rare protein-coding variants to 1,472 plasma proteins abundances measured via the Olink Explore 1536 assay in 50,829 UK Biobank human exomes. Through a variant-level exome-wide association study (ExWAS), we identified 3,674 rare and significant protein quantitative trait loci (pQTLs), of which 76% were undetected in a prior GWAS performed on the same cohort, and we found that rare pQTLs are less likely to be random in their variant effect annotation. In gene-based collapsing analyses, we identified an additional 166 significant gene-protein pQTL signals that were undetected through single-variant analyses. Of the total 456 protein-truncating variant (PTV)-driven cis-pQTLs in the gene-based collapsing analysis, 99.3% were associated with decreased protein levels. We demonstrate how this resource can identify allelic series and propose biomarkers for several candidate therapeutic targets, including GRN, HSD17B13, NLRC4, and others. Finally, we introduce a new collapsing analysis framework that combines PTVs with missense cis-pQTLs that are associated with decreased protein abundance to bolster genetic discovery statistical power. Our results collectively highlight a considerable role for rare variation in plasma protein abundance and demonstrate the utility of plasma proteomics in gene discovery and unravelling mechanisms of action.