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Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping

Author

Listed:
  • Karsten Suhre

    (Weill Cornell Medicine-Qatar, Education City
    Weill Cornell Medicine)

  • Guhan Ram Venkataraman

    (Seer, Inc., Redwood City)

  • Harendra Guturu

    (Seer, Inc., Redwood City)

  • Anna Halama

    (Weill Cornell Medicine-Qatar, Education City
    Weill Cornell Medicine)

  • Nisha Stephan

    (Weill Cornell Medicine-Qatar, Education City)

  • Gaurav Thareja

    (Weill Cornell Medicine-Qatar, Education City)

  • Hina Sarwath

    (Weill Cornell Medicine-Qatar, Education City)

  • Khatereh Motamedchaboki

    (Seer, Inc., Redwood City)

  • Margaret K. R. Donovan

    (Seer, Inc., Redwood City)

  • Asim Siddiqui

    (Seer, Inc., Redwood City)

  • Serafim Batzoglou

    (Seer, Inc., Redwood City)

  • Frank Schmidt

    (Weill Cornell Medicine-Qatar, Education City)

Abstract

Proteogenomics studies generate hypotheses on protein function and provide genetic evidence for drug target prioritization. Most previous work has been conducted using affinity-based proteomics approaches. These technologies face challenges, such as uncertainty regarding target identity, non-specific binding, and handling of variants that affect epitope affinity binding. Mass spectrometry-based proteomics can overcome some of these challenges. Here we report a pQTL study using the Proteograph™ Product Suite workflow (Seer, Inc.) where we quantify over 18,000 unique peptides from nearly 3000 proteins in more than 320 blood samples from a multi-ethnic cohort in a bottom-up, peptide-centric, mass spectrometry-based proteomics approach. We identify 184 protein-altering variants in 137 genes that are significantly associated with their corresponding variant peptides, confirming target specificity of co-associated affinity binders, identifying putatively causal cis-encoded proteins and providing experimental evidence for their presence in blood, including proteins that may be inaccessible to affinity-based proteomics.

Suggested Citation

  • Karsten Suhre & Guhan Ram Venkataraman & Harendra Guturu & Anna Halama & Nisha Stephan & Gaurav Thareja & Hina Sarwath & Khatereh Motamedchaboki & Margaret K. R. Donovan & Asim Siddiqui & Serafim Batz, 2024. "Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45233-y
    DOI: 10.1038/s41467-024-45233-y
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