Nanoparticle enriched mass spectrometry proteomics in British South Asians identifies novel variant-protein-disease mechanisms
Open accessAbstract
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 Grave’s 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.
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Several cis-pQTL signals driven by PAVs-most commonly missense variants-were observed on each platform.
“While the majority of cis-pQTL variants were non-coding on both platforms (Supplementary Fig. 8), we observe several cis-pQTL signals driven by protein altering variants (PAVs—most commonly missense variants) on each platform, raising concerns as to whether the signal captures abundances or differences in isoform, as has been shown in other studies18,24,25.”
From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [24]
The section “Protein altering variants and overlap with tissue gene expression loci explain pQTLs” (page unavailable) reports cis-pQTLs associated with protein-altering variants. “Cross-platform concordance of pQTLs” (page unavailable) also reports PAV-associated cis-pQTLs in comparisons with both Olink HT and SomaLogic 11k. The passages do not establish that missense variants were the most common PAVs on each platform, and they describe associations rather than showing that the PAVs drove those signals. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPlatform comparisons incorporating MS protein measures are already proving informative to further depict genetically encoded isoform differences and impacts of splicing on detected protein structures.
“Platform comparisons incorporating MS protein measures are already proving informative to further depict genetically encoded isoform differences and impacts of splicing on detected protein structures24,40,41, and will be especially important to expand across ancestrally diverse sets of participants.”
From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [24]
The Cross-platform concordance of pQTLs section reports genotype-dependent differences between MS and affinity-based measurements and identifies protein-altering variants as a possible explanation. It raises splicing QTLs producing different isoforms only as another possible explanation; it does not demonstrate effects of splicing on detected protein structures. The Technical variation section also reports little evidence that isoform-specific targeting explains poor cross-platform correlations. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPAV-driven cis-pQTL signals raise concerns as to whether the signal captures protein abundances or differences in isoform.
“While the majority of cis-pQTL variants were non-coding on both platforms (Supplementary Fig. 8), we observe several cis-pQTL signals driven by protein altering variants (PAVs—most commonly missense variants) on each platform, raising concerns as to whether the signal captures abundances or differences in isoform, as has been shown in other studies18,24,25.”
From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [24]
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Cross-ancestry comparison of aptamer and antibody protein measures
Nicholas, J. C., Katz, D. H., Tahir, U. A., Debban, C. L., Aguet, F., Blackwell, T., Bowler, R. P., Broadaway, K. A., Chen, J., Clish, C. B., et al. (2026) · Nature Communications · doi:10.1038/s41467-025-67814-1 · Cited by 13 · see citing works
- Authors
- Pietzner, M., Williamson, A., Hunt, K. A., Koprulu, M., Kohleick, L., Demircan, K., Genes & Health Research Team, Finer, S., Zanini, J. C., van Heel, D. A., & Langenberg, C.
- Affiliations
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Queen Mary University of London (GB)
- Corresponding author
- Pietzner, Maik
- ORCID
- Venue
- medRxiv
- Publisher
- openRxiv
- Published
- 2025-08-13
- OpenAlex
- W4413118258
- Cited by
- 4
- References
- 12
- Citations by year
- 2026: 3 · 2025: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- medRxiv (acceptedVersion, cc-by-nc-nd)
- Funders
- Queen Mary University of London
- Barts Charity (845/1796)
- National Institute for Health and Care Research (NIHR203330)
- King's College London
- European Commission
- Deutsche Forschungsgemeinschaft (547107463)
- Public Health England
- Barts Health NHS Trust
- Medical Research Council (MR/X009777/1, M009017, MR/X009920/1)
- HORIZON EUROPE European Research Council (101116072)
- Health Data Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- plasma proteomics, proteogenomics, protein quantitative trait loci, British South Asians, British Bangladeshis, British Pakistanis, non-coding variants, Graves' disease, B cell-mediated autoimmunity, cross-platform comparison, disease mechanisms, drug target identification, drug repurposing
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