Nanoparticle-enriched mass spectrometry proteomics in British South Asians identifies links between genetic variants, plasma protein levels and disease risk.

Understanding genetic variation associated with differences in plasma protein levels can elucidate human disease mechanisms. Here we demonstrate how untargeted nanoparticle-enriched mass spectrometry (MS)-based plasma proteomics delivers quantitatively and qualitatively different insights compared to two affinity-based assays in a sample of ~1,400 British South Asian individuals. We identify >1,200 significant locus-protein associations (P < 8.7 × 10-12; n = 895 cis-protein quantitative trait loci (pQTLs)), more than half of which have not been reported previously. Cross-platform comparison demonstrated that multiple platforms are required to capture the full spectrum of pQTLs of blood proteins. We combine proteogenomic results with evidence from multiple biological domains to suggest a potential role of 21 proteins in the pathology of 44 diseases, including a previously uncharacterized role of immunoglobulin λ variable 3-21 in the development of Graves' disease. Our results demonstrate the potential of MS-based blood proteomics in non-European ancestries for pQTL discovery and the need to consolidate proteogenomic evidence to confidently assign proteins to disease pathology.