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<p>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 &gt;1,200 significant locus–protein associations (<i>P</i> &lt; 8.7 × 10<sup>−12</sup>; <i>n</i> = 895 <i>cis</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月24日

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  • Maik Pietzner,
  • Alice Williamson,
  • Karen A. Hunt,
  • Mine Koprulu,
  • Leonhard Kohleick,
  • Kamil Demircan,
  • David A. van Heel,
  • Sarah Finer,
  • Julia Carrasco Zanini,
  • David A. van Heel,
  • Claudia Langenberg

摘要

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.