Nanoparticle enriched mass spectrometry proteomics in British South Asians identifies novel variant-protein-disease mechanisms

Understanding genetic variation underlying differences in plasma protein levels can elucidate human disease mechanisms, but prior evidence was almost entirely derived from white Europeans using protein-preselected affinity reagents. Here, we integrate exome sequencing and common non-coding variation with untargeted nanoparticle enriched mass spectrometry (MS)-based plasma proteomics (Seer Proteograph XT: n=8067 protein groups) in >1,400 British-Bangladeshi and British-Pakistani individuals. We gain quantitatively and qualitatively different insights compared to two affinity-based assays in the same samples (SomaLogic 11k: n=9685 and Olink HT: n=5416 proteins), both in terms of proteins covered, and new proteogenomic insights into disease biology. Considering both additive and non-additive genetic effects, we identify >1,200 significant variant-protein associations (n=895 cis-protein quantitative trait loci (pQTL)), half of which are novel. Cross-platform comparison demonstrated that inconsistencies in pQTL discovery are mostly explained by technical variation, and that multiple platforms are required to capture the full spectrum of pQTLs of blood proteins. We integrate proteogenomic evidence with orthogonal human genetic, experimental, and single cell expression data to consolidate a potential role of 21 proteins in the pathology of 44 diseases: e.g., a novel role of high IGLV3-21 in the development of Graves disease elucidating B-cell mediated autoimmunity. Our results demonstrate the potential of MS-based blood proteomics in diverse ancestries for pQTL discovery, including functional characterization of missense variants, and the need to consolidate evidence from multiple biological domains to confidently assign proteins to disease pathology to guide drug target identification and drug repurposing.